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Minimal Pharmacokinetic Interaction between the Human Immunodeficiency Virus Nonnucleoside Reverse Transcriptase Inhibitor Etravirine and the Integrase Inhibitor Raltegravir in Healthy Subjects▿

Anderson, Matt S.; Kakuda, Thomas N.; Hanley, William; Miller, Jutta; Kost, James T.; Stoltz, Randall; Wenning, Larissa A.; Stone, Julie A.; Hoetelmans, Richard M. W.; Wagner, John A.; Iwamoto, Marian
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
EN
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28.18%
Etravirine, a next-generation nonnucleoside reverse transcriptase inhibitor, and raltegravir, an integrase strand transfer inhibitor, have separately demonstrated potent activity in treatment-experienced, human immunodeficiency virus (HIV)-infected patients. An open-label, sequential, three-period study with healthy, HIV-seronegative subjects was conducted to assess the two-way interaction between etravirine and raltegravir for potential coadministration to HIV-infected patients. In period 1, 19 subjects were administered 400 mg raltegravir every 12 h (q12 h) for 4 days, followed by a 4-day washout; in period 2, subjects were administered 200 mg etravirine q12 h for 8 days; and in period 3, subjects were coadministered 400 mg raltegravir and 200 mg etravirine q12 h for 4 days. There was no washout between periods 2 and 3. Doses were administered with a moderate-fat meal. Etravirine had only modest effects on the pharmacokinetics of raltegravir, while raltegravir had no clinically meaningful effect on the pharmacokinetics of etravirine. For raltegravir coadministered with etravirine relative to raltegravir alone, the geometric mean ratio (GMR) and 90% confidence interval (CI) were 0.90 and 0.68 to 1.18, respectively, for the area under the concentration curve from 0 to 12 h (AUC0-12)...

Etravirine: a second-generation NNRTI for treatment-experienced adults with resistant HIV-1 infection

Minuto, Joshua J; Haubrich, Richard
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/11/2008 EN
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Etravirine, a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), was approved in the USA in January, 2008, with approval in Europe expected later this year. It is dosed at 200 mg (two 100 mg tablets) twice daily foll owing a meal. It is approved for treatment of HIV-1 infection in adults failing a stable antiretroviral regimen with resistance to other NNRTIs and other antiretroviral agents. Etravirine is active against HIV with single mutations in the reverse transcriptase (e.g., K103N) that confer class resistance to first-generation NNRTIs. Clinical efficacy in Phase III trials has been demonstrated for up to 48 weeks of follow-up. In these Phase III trials, rash was the only adverse event that was significantly more prevalent with etravirine than with placebo. Etravirine has a tolerability and safety profile comparable to placebo with the exception of rash. Rash was generally grade 1 or 2, was not associated with prior NNRTI-related rash, was more common in women than in men, appeared a median of 12 days after treatment initiation and resolved spontaneously with continued therapy. Etravirine is the first agent in the NNRTI class that can be used for HIV-1 virus with resistance to other NNRTIs owing to a higher genetic barrier to resistance.

Profile of etravirine for the treatment of HIV infection

Tseng, Alice; MacArthur, Rodger D
Fonte: Dove Medical Press Publicador: Dove Medical Press
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
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Etravirine is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with the advantages of in vitro potency against many strains of virus resistant to efavirenz and nevirapine, as well as a higher genetic barrier to resistance. Etravirine is indicated for use in treatment-experienced patients, and the approved dose in adults is 200 mg twice daily. Etravirine should be administered after a meal as bioavailability is significantly reduced when taken in the fasting state. Etravirine is a substrate of CYP3A4, CYP2C9, CYP2C19, and uridine diphosphate glucuronyltransferase, and induces CYP3A4, weakly inhibits CYP2C9 and moderately inhibits CYP2C19. Etravirine may be coadministered with nucleoside/tide reverse transcriptase inhibitors, raltegravir and boosted darunavir, lopinavir, and saquinavir without dosage adjustment. Etravirine should not be given with other NNRTIs, unboosted protease inhibitors, and atazanavir/ritonavir, tipranavir/ritonavir, and fosamprenavir/ritonavir due to unfavorable drug interactions. In randomized, controlled trials, twice daily etravirine combined with darunavir/ritonavir plus optimized background therapy demonstrated better efficacy compared to darunavir/ritonavir plus optimized background therapy alone in treatment-experienced populations out to 96 weeks follow-up. The main etravirine-associated toxicity is mild to moderate self-limiting rash...

N348I in HIV-1 Reverse Transcriptase Decreases Susceptibility to Tenofovir and Etravirine in Combination with Other Resistance Mutations

Sluis-Cremer, Nicolas; Moore, Katie; Radzio, Jessica; Sonza, Secondo; Tachedjian, Gilda
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 16/01/2010 EN
Relevância na Pesquisa
27.71%
We previously demonstrated that N348I in HIV-1 reverse transcriptase confers zidovudine and nevirapine resistance. However, both of these inhibitors are currently infrequently used in developed countries and the impact of N348I on newer RT inhibitors, such as tenofovir and etravirine, is unknown. In this study, we demonstrate that N348I alone confers no resistance to tenofovir and low-level resistance to etravirine. However, N348I significantly decreases tenofovir susceptibility when combined with thymidine analogue mutations and etravirine susceptibility when combined with Y181C.

LC-MS/MS determination of etravirine in rat plasma and its application in pharmacokinetic studies

Abobo, Cyril; Wu, Lei; John, Jyothy; Joseph, Mathew K.; Bates, Theodore R.; Liang, Dong
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.94%
Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that is active against NNRT-resistant HIV-1. A simple, sensitive, and specific LC-MS/MS method was developed and validated for the analysis of etravirine in rat plasma using itraconazole as the internal standard. The analytes were extracted with ethyl acetate and chromatographed on a reverse-phase XTerra MS C18 column. Elution was achieved with a mobile phase gradient varying the proportion of a 2 mM ammonium acetate aqueous solution containing 0.1% formic acid (solvent A) and a 0.1% formic acid in methanol solution (solvent B) at a flow rate of 300 μL/min. The analytes were monitored by tandem-mass spectrometry with positive electrospray ionization. The precursor/product transitions (m/z) in the positive ion mode were 435.9→163.6 and 706.7→392.6 for etravirine and the internal standard, respectively. Calibration curves were linear over the etravirine rat plasma concentration range of 1 ng/mL to 100 ng/mL. The inter- and intra-day accuracy and precision were within ±10%. The assay has been successfully used for pharmacokinetic evaluation of etravirine using the rat as an animal model.

Interaction Potential of Etravirine with Drug Transporters Assessed In Vitro ▿

Zembruski, Nadine Cécile Luise; Haefeli, Walter Emil; Weiss, Johanna
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.94%
Etravirine is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of HIV-1 infections. ABC transporters potentially mediate clinically relevant drug-drug interactions. We assessed substrate characteristics and the inhibitory and inductive potential of etravirine on ABC transporters. Etravirine did not inhibit P-gp/ABCB1 and was not transported by the tested ABC transporters but was a potent inhibitor of BCRP/ABCG2. Etravirine induced several ABC transporters, especially BCRP/ABCG2. These data demonstrate that etravirine has the potential for drug-drug interactions by modulation of expression and function of several ABC transporters.

Darunavir, Ritonavir, and Etravirine Pharmacokinetics in the Cervicovaginal Fluid and Blood Plasma of HIV-Infected Women▿

Patterson, Kristine; Jennings, Steven; Falcon, Ron; Mrus, Joseph; Kashuba, Angela
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.84%
We report darunavir, ritonavir, and etravirine pharmacokinetics in cervicovaginal fluid and blood plasma for women from the Gender, Race and Clinical Experience (GRACE) study. Eight women received darunavir-ritonavir (600/100 mg) twice daily (b.i.d.); two also received etravirine (200 mg) b.i.d. Week 4 paired blood plasma and cervicovaginal fluid samples were collected over 12 h. Darunavir and etravirine cervicovaginal fluid exposures were higher than blood plasma exposures; ritonavir cervicovaginal fluid exposure was lower than blood plasma exposure. The high exposures of darunavir and etravirine in cervicovaginal fluid warrant further evaluation of these drugs for use in HIV-1 prevention.

Pharmacokinetic Interactions of Maraviroc with Darunavir-Ritonavir, Etravirine, and Etravirine-Darunavir-Ritonavir in Healthy Volunteers: Results of Two Drug Interaction Trials▿†

Kakuda, Thomas N.; Abel, Samantha; Davis, John; Hamlin, Julia; Schöller-Gyüre, Monika; Mack, Rebecca; Ndongo, Noella; Petit, Wendy; Ridgway, Caroline; Sekar, Vanitha; Tweedy, Sarah; Hoetelmans, Richard M. W.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /05/2011 EN
Relevância na Pesquisa
28.21%
The effects of darunavir-ritonavir at 600 and 100 mg twice daily (b.i.d.) alone, 200 mg of etravirine b.i.d. alone, or 600 and 100 mg of darunavir-ritonavir b.i.d. with 200 mg etravirine b.i.d. at steady state on the steady-state pharmacokinetics of maraviroc, and vice versa, in healthy volunteers were investigated in two phase I, randomized, two-period crossover studies. Safety and tolerability were also assessed. Coadministration of 150 mg maraviroc b.i.d. with darunavir-ritonavir increased the area under the plasma concentration-time curve from 0 to 12 h (AUC12) for maraviroc 4.05-fold relative to 150 mg of maraviroc b.i.d. alone. Coadministration of 300 mg maraviroc b.i.d. with etravirine decreased the maraviroc AUC12 by 53% relative to 300 mg maraviroc b.i.d. alone. Coadministration of 150 mg maraviroc b.i.d. with etravirine-darunavir-ritonavir increased the maraviroc AUC12 3.10-fold relative to 150 mg maraviroc b.i.d. alone. Maraviroc did not significantly affect the pharmacokinetics of etravirine, darunavir, or ritonavir. Short-term coadministration of maraviroc with darunavir-ritonavir, etravirine, or both was generally well tolerated, with no safety issues reported in either trial. Maraviroc can be coadministered with darunavir-ritonavir...

Connection Domain Mutations in HIV-1 Reverse Transcriptase Do Not Impact Etravirine Susceptibility and Virologic Responses to Etravirine-Containing Regimens▿†

Gupta, Soumi; Vingerhoets, Johan; Fransen, Signe; Tambuyzer, Lotke; Azijn, Hilde; Frantzell, Arne; Paredes, Roger; Coakley, Eoin; Nijs, Steven; Clotet, Bonaventura; Petropoulos, Christos J.; Schapiro, Jonathan; Huang, Wei; Picchio, Gaston
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /06/2011 EN
Relevância na Pesquisa
28.23%
Connection domain mutations (CDMs) in HIV-1 reverse transcriptase (RT) alter susceptibility to some nucleoside/nonnucleoside RT inhibitors (NRTIs/NNRTIs). Their effects on susceptibility and virologic responses to etravirine were analyzed. Seventeen CDMs were evaluated: L283I, E312Q, G333D, G333E, G335C, G335D, N348I, A360I, A360T, A360V, V365I, T369I, A371V, A376S, I393L, E399D, and E399G. CDM prevalence and effects on virologic responses were analyzed retrospectively using clinical data. The effects on etravirine susceptibility were assessed in clinical samples and confirmed using site-directed mutants. The most prevalent CDMs (>10%) were A371V, E399D, A376S, N348I, A360T, G333E, and L283I. CDM presence was positively correlated with thymidine analogue-associated mutations, but not with NNRTI resistance-associated mutations (RAMs). The presence or number of CDMs did not significantly reduce etravirine susceptibility, although small reductions were seen in samples with G333D, N348I, A360V, T369I, and A376S. N348I, E399G, and N348I/T369I were associated with reduced etravirine susceptibility when present with K103N, L100I, or Y181C. N348I or T369I was associated with reduced etravirine susceptibility when present with K101P or K103R/V179D. Virologic responses to an etravirine-containing regimen were slightly diminished when G333D...

Interaction of Reverse Transcriptase (RT) Mutations Conferring Resistance to Lamivudine and Etravirine: Effects on Fitness and RT Activity of Human Immunodeficiency Virus Type 1 ▿

Hu, Zixin; Kuritzkes, Daniel R.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /11/2011 EN
Relevância na Pesquisa
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Resistance to the nonnucleoside reverse transcriptase inhibitors etravirine and rilpivirine (RPV) is conferred by the E138K mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). Clinical trials of RPV administered with lamivudine or emtricitabine showed the emergence of E138K together with M184I, which confers lamivudine and emtricitabine resistance in most patients with virologic failure. To understand why M184I was favored over M184V, we determined the drug susceptibility, infectivity, relative fitness, and reverse transcriptase activity of HIV-1 carrying E138K/M184I or E138K/M184V mutations. Whereas the replication capacity (RC) of the single mutants was reduced compared to that of the wild type (WT), the RC of the two double mutants was comparable to that of the WT in the absence of drug. The RC of the E138K/M184I mutant in the presence of etravirine was significantly greater than that of the E138K and E138K/M184V mutants; the RC of the double mutants was greater than that of the M184I or M184V mutant. Fitness profiles and growth competition experiments showed that the E138K/M184I mutant had a significant replicative advantage over the E138K/M184V mutant in the presence of etravirine and lamivudine. The virion-associated RT activity of the E138K...

Role of etravirine in the management of treatment-experienced patients with human immunodeficiency virus type 1

Viani, Rolando M
Fonte: Dove Medical Press Publicador: Dove Medical Press
Tipo: Artigo de Revista Científica
Publicado em 28/06/2010 EN
Relevância na Pesquisa
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Etravirine is an oral diarylpyrimidine compound, a second-generation human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitor (NNRTI) with expanded antiviral activity against NNRTI-resistant HIV-1, to be used in combination therapy for treatment-experienced patients. Compared with first-generation NNRTIs, etravirine has a high genetic barrier to resistance, and is better tolerated without the neuropsychiatric and hepatic side effects of efavirenz and nevirapine, respectively. Its safety profile is comparable to placebo with the exception of rash, which has been mild and self-limited in the great majority of patients. In phase III clinical trials among treatment-experienced patients harboring NNRTI-resistant HIV-1, etravirine in combination with an optimized background regimen (OBR) that included ritonavir-boosted darunavir demonstrated superior antiviral activity than the control OBR. In addition, patients on the etravirine arm had fewer AIDS-defining conditions, hospitalizations, and lower mortality compared with the OBR control arm.

Pharmacokinetics and Pharmacodynamics of Darunavir and Etravirine in HIV-1–Infected, Treatment-Experienced Patients in the Gender, Race, and Clinical Experience (GRACE) Trial

Kakuda, Thomas; Sekar, Vanitha; Vis, Peter; Coate, Bruce; Ryan, Robert; Anderson, David; De La Rosa, Guy; Mrus, Joseph
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
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Objectives. Evaluation of pharmacokinetics and pharmacodynamics of darunavir and etravirine among HIV-1–infected, treatment-experienced adults from GRACE, by sex and race. Methods. Patients received darunavir/ritonavir 600/100mg twice daily plus other antiretrovirals, which could include etravirine 200mg twice daily. Population pharmacokinetics for darunavir and etravirine were determined over 48 weeks and relationships assessed with virologic response and safety. Rich sampling for darunavir, etravirine, and ritonavir was collected in a substudy at weeks 4, 24, and 48. Results. Pharmacokinetics were estimated in 376 patients for darunavir and 190 patients for etravirine. Median darunavir AUC12h and C0h were 60,642ng·h/mL and 3624ng/mL, respectively; and for etravirine were 4183ng · h/mL and 280ng/mL, respectively. There were no differences in darunavir or etravirine AUC12h or C0h by sex or race. Age, body weight, or use of etravirine did not affect darunavir exposure. No relationships were seen between darunavir pharmacokinetics and efficacy or safety. Patients with etravirine exposure in the lowest quartile generally had lower response rates. Rich sampling showed no time-dependent relationship for darunavir, etravirine...

Etravirine Concentrations in the Cervicovaginal Compartment in HIV-1-Infected Women Receiving Etravirine-Containing Antiretroviral Therapy: DIVA 02 Study

Clavel, C.; Peytavin, G.; Tubiana, R.; Soulié, C.; Courbon, E.; Crenn-Hebert, C.; Ichou, H.; Blanc, C.; Schneider, L.; Katlama, C.; Marcelin, A.-G.; Mandelbrot, L.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /07/2012 EN
Relevância na Pesquisa
28.01%
We studied the penetration of etravirine and HIV shedding in the genital tract among 12 HIV-1-infected women receiving an etravirine-containing regimen who had <40 copies/ml blood plasma (BP) HIV RNA. None of the cervicovaginal fluid (CVF) samples showed detectable HIV RNA. Median etravirine concentrations were 663 ng/ml in BP and 857 ng/ml in CVF, with a CVF/BP etravirine ratio of approximately 1.2. This good penetration of etravirine may contribute to the control of viral replication in the female genital tract.

Herb-Drug Interaction between Echinacea purpurea and Etravirine in HIV-Infected Patients

Moltó, José; Valle, Marta; Miranda, Cristina; Cedeño, Samandhy; Negredo, Eugenia; Clotet, Bonaventura
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /10/2012 EN
Relevância na Pesquisa
28.18%
The aim of this open-label, fixed-sequence study was to investigate the potential of the botanical supplement Echinacea purpurea to interact with etravirine, a nonnucleoside reverse transcriptase inhibitor of HIV. Fifteen HIV-infected patients receiving antiretroviral therapy with etravirine (400 mg once daily) for at least 4 weeks were included. E. purpurea root/extract-containing capsules were added to the antiretroviral treatment (500 mg every 8 h) for 14 days. Etravirine concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, 12, and 24 h after a morning dose of etravirine on day 0 and etravirine plus E. purpurea on day 14. Individual etravirine pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 by means of the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 46 years (interquartile range, 41 to 50), and the median body weight was 76 kg (interquartile range, 68 to 92). Echinacea was well tolerated, and all participants completed the study. The GMR for etravirine coadministered with E. purpurea relative to etravirine alone was 1.07 (90% CI, 0.81 to 1.42) for the maximum concentration...

Effects of Etravirine on the Pharmacokinetics of the Integrase Inhibitor S/GSK1265744

Ford, Susan L.; Gould, Elizabeth; Chen, Shuguang; Lou, Yu; Dumont, Etienne; Spreen, William; Piscitelli, Stephen
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /01/2013 EN
Relevância na Pesquisa
27.71%
HIV integrase inhibitors such as raltegravir and elvitegravir halt HIV progression, but treatment-emergent resistance and cross-resistance have been observed. The nonnucleoside reverse transcriptase inhibitor etravirine (ETR) may be used in combination with integrase inhibitors in patients with drug resistance. This single-center, open-label, two-period, single-sequence crossover study evaluated the effects of ETR coadministration on the pharmacokinetic profile of S/GSK1265744, an investigational integrase inhibitor in phase 2 studies. Healthy subjects received 30 mg of S/GSK1265744 alone once daily for 10 days (period 1) and in combination with 200 mg of ETR twice daily for 14 days (period 2). Serial plasma samples for pharmacokinetic analyses were collected on day 10 during period 1 and on day 14 during period 2. All treatments were well tolerated. Etravirine had no effects on S/GSK1265744 geometric mean ratios of the area under the curve from time zero until the end of the dosing interval (1.01; 90% confidence interval [CI], 0.956 to 1.06), of the maximum observed plasma concentration (1.04; 90% CI, 0.987 to 1.09), or of the plasma concentration at the end of the dosing interval (0.999; 90% CI, 0.942 to 1.06). Etravirine pharmacokinetics (PK) parameters observed following coadministration with S/GSK1265744 were in the range of historical values reported for ETR alone in healthy subjects. These results indicate that 30 mg of S/GSK1265744 for 10 days as monotherapy followed by an additional 14 days in combination with ETR was well tolerated in healthy subjects and that no dose adjustment of S/GSK1265744 is required when it is coadministered with ETR.

The role of etravirine in the management of treatment-experienced pediatric patients with HIV

Osterholzer, Danielle
Fonte: Dove Medical Press Publicador: Dove Medical Press
Tipo: Artigo de Revista Científica
Publicado em 10/04/2013 EN
Relevância na Pesquisa
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Pediatric patients infected with human immunodeficiency virus (HIV) are now living longer, healthier lives due to the advent of combined antiretroviral (ARV) therapy, including regimens that often contain non-nucleoside reverse transcriptase inhibitors (NNRTIs). However, first-generation NNRTIs such as nevirapine (NVP) and efavirenz (EFV) have a low genetic barrier to resistance, and both drugs can become ineffective with a single viral point mutation. New agents with activity against resistant viral strains must be available to salvage children and adolescents with virologic failure after NNRTI use. One such drug, etravirine, an oral second-generation NNRTI approved for use in the US in heavily treatment-experienced HIV-1-infected adults in 2008, is accumulating data in this younger population. Etravirine became approved by the US Food and Drug Administration in early 2012 to be used in combination with other ARV medications in HIV-1-infected children aged 6 years to <18 years who are failing their regimens with HIV-1 strains resistant to NNRTIs and other ARVs. This approval was largely based on data from a prospective, open-label, phase II clinical trial in this age group prescribed etravirine at 5.2 mg/kg twice daily (up to the adult dose of 200 mg twice daily) in combination with an investigator-selected optimized background regimen. Currently available 48-week follow-up data show complete viral suppression (<50 copies/mL) in 56% of the patients...

Etravirine as a Switching Option for Patients with HIV RNA Suppression: A Review of Recent Trials

Nelson, Mark; Hill, Andrew; van Delft, Yvon; Moecklinghoff, Christiane
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
28.21%
Unlike other nonnucleoside reverse transcriptase inhibitors, etravirine is only approved for use in treatment-experienced patients. In the DUET 1 and 2 trials, 1203 highly treatment-experienced patients were randomized to etravirine or placebo, in combination with darunavir/ritonavir and optimized background treatment. In these trials, etravirine showed significantly higher rates of HIV RNA suppression when compared with placebo (61% versus 40% at Week 48). There was no significant rise of lipids or neuropsychiatric adverse events, but there was an increase in the risk of rash with etravirine treatment. In the SENSE trial, which evaluated etravirine and efavirenz in 157 treatment-naïve patients in combination with 2 nucleoside analogues, there was a lower risk of lipid elevations and neuropsychiatric adverse events with etravirine when compared to efavirenz. Etravirine has been evaluated in three randomized switching studies. In the SSAT029 switch trial, 38 patients who had neuropsychiatric adverse events possibly related to efavirenz showed an improvement in these after switching to etravirine. The Swiss Switch-EE recruited 58 individuals without neuropsychiatric adverse events who were receiving efavirenz, and no benefit was shown when switching to etravirine. In the Spanish ETRA-SWITCH trial (n = 46)...

Pharmacokinetics of Etravirine Combined with Atazanavir/Ritonavir and a Nucleoside Reverse Transcriptase Inhibitor in Antiretroviral Treatment-Experienced, HIV-1-Infected Patients

Orrell, Catherine; Felizarta, Franco; Nell, André; Kakuda, Thomas N.; Lavreys, Ludo; Nijs, Steven; Tambuyzer, Lotke; Van Solingen-Ristea, Rodica; Tomaka, Frank L.
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.94%
Objectives. TEACH (NCT00896051) was a randomized, open-label, two-arm Phase II trial to investigate the pharmacokinetic interaction between etravirine and atazanavir/ritonavir and safety and efficacy in treatment-experienced, HIV-1-infected patients. Methods. After a two-week lead-in of two nucleoside reverse transcriptase inhibitors (NRTIs) and atazanavir/ritonavir 300/100 mg, 44 patients received etravirine 200 mg bid with one NRTI, plus atazanavir/ritonavir 300/100 mg or 400/100 mg qd (n = 22 each group) over 48 weeks. Results. At steady-state etravirine with atazanavir/ritonavir 300/100 mg qd or 400/100 mg qd decreased atazanavir Cmin⁡ by 18% and 9%, respectively, with no change in AUC24 h or Cmax⁡ versus atazanavir/ritonavir 300/100 mg qd alone (Day −1). Etravirine AUC12 h was 24% higher and 16% lower with atazanavir/ritonavir 300/100 or 400/100 mg qd, respectively, versus historical controls. At Week 48, no significant differences were seen between the atazanavir/ritonavir groups in discontinuations due to adverse events (9.1% each group) and other safety parameters, the proportion of patients with viral load <50 copies/mL (intent-to-treat population, noncompleter = failure) (50.0%, atazanavir/ritonavir 300/100 mg qd versus 45.5%...

The Role of Second Generation Antiretroviral Drugs in HIV-1 Subtype B and non-B Variants Harboring Natural Polymorphisms and Drug Resistance Mutations.

Asahchop, Eugene L.
Fonte: Université de Montréal Publicador: Université de Montréal
Tipo: Thèse ou Mémoire numérique / Electronic Thesis or Dissertation
EN
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Cette thèse traite de la résistance du VIH-1 aux antirétroviraux, en particulier de l'activité antivirale de plusieurs inhibiteurs non nucléosidiques de la transcriptase inverse (INNTI) ainsi que des inhibiteurs de protéase (IP). Nous avons exploré l’émergence et la spécificité des voies de mutations qui confèrent la résistance contre plusieurs nouveaux INNTI (étravirine (ETR) et rilpivirine (RPV)) (chapitres 2 et 3). En outre, le profil de résistance et le potentiel antirétroviral d'un nouvel IP, PL-100, est présenté dans les chapitres 4 et 5. Pour le premier projet, nous avons utilisé des sous-types B et non-B du VIH-1 pour sélectionner des virus résistants à ETR, et ainsi montré que ETR favorise l’émergence des mutations V90I, K101Q, E138K, V179D/E/F, Y181C, V189I, G190E, H221H/Y et M230L, et ce, en 18 semaines. Fait intéressant, E138K a été la première mutation à émerger dans la plupart des cas. Les clones viraux contenant E138K ont montré un faible niveau de résistance phénotypique à ETR (3,8 fois) et une diminution modeste de la capacité de réplication (2 fois) par rapport au virus de type sauvage. Nous avons également examiné les profils de résistance à ETR et RPV dans les virus contenant des mutations de résistance aux INNTI au début de la sélection. Dans le cas du virus de type sauvage et du virus contenant la mutation unique K103N...

Marked increase in etravirine and saquinavir plasma concentrations during atovaquone/proguanil prophylaxis

Tommasi, Chiara; Bellagamba, Rita; Tempestilli, Massimo; D'Avolio, Antonio; Gallo, Anna L; Ivanovic, Jelena; Nicastri, Emanuele; Pucillo, Leopoldo P; Narciso, Pasquale
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em 21/05/2011 EN
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The case of a 32-year-old Caucasian female with multi-drug resistant HIV-1 subtype B infection treated with a salvage regimen including maraviroc, raltegravir, etravirine and unboosted saquinavir who started atovaquone/proguanil prophylaxis, is reported. The potential interactions between atovaquone/proguanil and these anti-retroviral drugs are investigated. Pharmacokinetic analyses documented a marked increase in etravirine and saquinavir plasma concentrations (+55% and +274%, respectively), but not in raltegravir and maraviroc plasma concentrations. The evidence that atovaquone/proguanil significantly interacts with etravirine and saquinavir, but not with raltegravir and maraviroc, suggests that the mechanism of interaction is related to cytochrome P450.