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Rates of modification and interruption were still high in recent years, particularly in the first year of ART. The decreased rate of modification found in patients treated with Rilpivirine may be attributed to selection of patients according to guidelines.
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There is a shortage of pharmacokinetic data in the highly variable population of HIV-infected children. Selected pharmacology studies should be undertaken to improve pediatric dose guidance of existing antiretroviral drugs. Therapeutic drug monitoring is a useful tool to optimize treatment in HIV-infected children. More data are needed, however, to establish child-specific reference values.
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We analyzed data on ART naïve, non-pregnant patients, ≥ 18 years old without tuberculosis co-infection, initiating tenofovir with lamivudine and either nevirapine or efavirenz between April 1, 2010 and July 31, 2011 (when South Africa's public-sector use of tenofovir began) at Themba Lethu Clinic in South Africa. We measured virologic suppression (viral load <400 copies/ml), virologic failure (2 consecutive viral loads >1000 copies/ml), and attrition (death/loss to follow-up) all at 12 months after ART initiation. Modified Poisson regression with robust error estimation was used to estimate risk ratios (RR) and 95% confidence intervals (CI) for predictors of each outcome.
Our results support the notion that, among patients prescribed tenofovir and lamivudine, virologic failure is more common among those taking nevirapine than among those taking efavirenz. Longer-term follow up and larger studies will be needed to confirm this finding.
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The inclusion criteria were children who were <18 years and receiving NNRTI-based ART. Plasma HIV-1 RNA and CD4 were monitored every 6 months. Virologic failure was defined as plasma HIVRNA >1000 copies/mL.
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Dihydroartemisinin (DHA)-piperaquine is promising for malaria chemoprevention in pregnancy. We assessed impacts of pregnancy and efavirenz-based antiretroviral therapy on exposure to DHA and piperaquine in pregnant Ugandan women. Intensive sampling was performed at 28 weeks gestation in 31 HIV-uninfected pregnant women, in 27 HIV-infected pregnant women receiving efavirenz, and in 30 HIV-uninfected non-pregnant women. DHA peak concentration and area under the concentration time curve (AUC0-8hr ) were 50% and 47% lower, respectively, and piperaquine AUC0-21d was 40% lower in pregnant women compared to non-pregnant women. DHA AUC0-8hr and piperaquine AUC0-21d were 27% and 38% lower, respectively in pregnant women receiving efavirenz compared to HIV-uninfected pregnant women. Exposure to DHA and piperaquine were lower among pregnant women and particularly in women on efavirenz, suggesting a need for dose modifications. The study of modified dosing strategies for these populations is urgently needed. This article is protected by copyright. All rights reserved.
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We evaluated the role of these mutations in NNRTI hypersusceptibility by site-directed mutagenesis and phenotypic analysis of HIV-1 recombinants.
This was a prospective randomized clinical trial comparing the efficacy of HBV monotherapy with FTC versus TDF/FTC combination therapy in ARV-naive HIV-HBV coinfection. HIV-HBV-coinfected patients initiating ARV were randomized to either FTC/zidovudine/efavirenz (EFV; n=6) or TDF/FTC/EFV (n=10). The primary end point was the time-weighted area under the curve (TWAUC) of HBV DNA at 48 weeks.
To review the pharmacology, safety, and efficacy of dolutegravir, an integrase strand-transfer inhibitor (INSTI), and to discuss its role in the treatment of HIV-1-infected patients.
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To describe the virological and pharmacological outcomes of three different recommended once-daily first-line regimens in a cross-sectional analysis within an observational cohort using ultra-sensitive HIV quantification.
OBJECTIVE: This study was designed to investigate the pharmacokinetic effects of coadministration of saquinavir/ritonavir with efavirenz at steady state. METHODS: Healthy volunteers in this open-label, two-arm, one-sequence, two-period crossover study (planned enrollment of 40 participants) were randomized to one of two treatment arms: those in Arm 1 were scheduled to receive saquinavir/ritonavir 1,000/100 mg orally twice daily for 29 days and efavirenz 600 mg orally once daily starting on day 15 and continuing through day 29; participants randomized to Arm 2 were to receive efavirenz once daily for 29 days and saquinavir/ritonavir 1,000/100 mg twice daily starting on day 15 through day 29. Assessments included vital signs, laboratory analyses, electrocardiography, and blood levels of total saquinavir, ritonavir, and efavirenz. Pharmacokinetic parameters included C(max) (maximum observed plasma concentration), t(max) (time to reach the maximum observed plasma concentration), (apparent elimination half-life), and AUC(0-tau) (area-under-the-plasma-concentration-time curve over one dosing interval). RESULTS: Eight participants (four in each arm) were enrolled; only two (one from each treatment arm) reached day 15 of the study and received the concurrent initial doses of saquinavir/ritonavir and efavirenz. The study was terminated prematurely after these two participants experienced nonserious adverse events. The participant in Arm 1 experienced mild abdominal discomfort, diarrhea, sleep disorder, and headache and the participant in Arm 2 experienced moderate-intensity abdominal pain and mild vomiting with leukocytosis accompanied by elevated pancreatic and hepatic enzymes (aspartate aminotransferase and alanine aminotransferase values of 2-fold and 3.5-fold the upper limit of normal, respectively). Both participants recovered completely following treatment discontinuation. Only limited pharmacokinetic data were generated on these two participants. CONCLUSIONS: The early termination of this study precluded drawing any definitive conclusions regarding the pharmacokinetics at steady state of coadministered saquinavir/ritonavir and efavirenz.
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Open-label, nonrandomized, clinical trial.
HIV-infected children receiving a twice-daily lopinavir/ritonavir-based regimen and with an HIV-1 RNA viral load (VL) <40 copies/mL for at least 3 months were enrolled. Intensive steady-state 12 h blood sampling for PK assessment was performed at enrolment. Immediately afterwards, the lopinavir/ritonavir dose was changed to once daily with the equivalent daily dose, and intensive steady-state 24 h blood sampling was repeated 2 weeks later. If the lopinavir C(trough) was <1.0 μg/mL, the lopinavir/ritonavir dose was increased by 20%-30% and C(trough) measurement repeated. CD4 cell counts and VL were determined at baseline and at 12, 24 and 48 weeks.
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Neurocognitive impairment remains prevalent, despite combination antiretroviral therapy (cART). Differences between changes in cerebral function and alternative cARTs have not been prospectively assessed.
To determine the kinetics and mechanism of hydrolysis of efavirenz [(S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one] in aqueous solutions.
DuPont Merck opened an expanded access program for Sustiva (DMP 266). The program is open to AIDS patients with T-cell counts less than 50 who are failing other antiretroviral therapies. Little data exists on the safety of the drug and there are cross-resistance issues. Adefovir (Preveon) is available through Gilead's unlimited expanded access program for persons with T-cell counts below 50 and viral load greater than 30,000. Unlike Sustiva, an NNRTI, adefovir is a nucleotide analogue. Adefovir appears to be effective against several viruses; however, early reports suggest significant side effects, including kidney damage. Contact information is included for both programs.
Interindividual variability in trough concentrations of NNRTI and PI among HIV-infected adults is large in routine clinical practice, with drug concentrations being outside the therapeutic window in a significant proportion of patients. Therapeutic drug monitoring may be useful to guide antiretroviral therapy in clinical practice.
A randomized, double-blind, multicenter phase IIb/III study with an open-label extension phase.
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The recent introduction of integrase inhibitors (INIs) into the HIV treatment armentarium has had a significant impact on HIV treatment. However, at present, raltegravir twice daily is the only licensed INI featuring a lower genetic barrier compared with boosted protease inhibitors. S/GSK1349572 represents a new INI in current development. It is a once-daily, unboosted INI with low pharmacokinetic variability and predictable exposure-response relationship. Phase IIb studies in antiretroviral-naïve patients have demonstrated non-inferiority to efavirenz-based HIV therapy. Phase II studies in INI-experienced patients show partially retained activity in vivo. Overall, the safety profile of S/GSK1349572 in all studies completed has been very favorable.
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The Basel cocktail was well tolerated, and bioequivalence tests showed no evidence of mutual interactions between the probe drugs. In plasma, single timepoint metabolic ratios at 2 h (for CYP2C19 and CYP3A4) or at 8 h (for the other isoforms) after dosing showed high correlations with corresponding area under the concentration-time curve (AUC) ratios (AUC0-24h parent/AUC0-24h metabolite) and are proposed as simple phenotyping metrics. Metabolic ratios in dried blood spots (for CYP1A2 and CYP2C19) or in saliva samples (for CYP1A2) were comparable to plasma ratios and offer the option of minimally invasive or non-invasive phenotyping of these isoforms.
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The primary end point--viral load decay rate per day--was 0.13 log10 RNA copies/ml per day. Over 7 days, we observed a median 0.89 log10 decrease in HIV-1 viral load; seven individuals (44%) had a decrease of > 1 log10. The most significant adverse effects were grade I diarrhoea (31%) and a mild headache (25%). Steady-state drug levels were achieved by day 6.
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Effective contraception has been widely promoted for HIV-positive women. However, there are limited data on the interactions between combined hormonal contraceptives and nonnucleoside reverse transcriptase inhibitors .
Prevalence of etravirine genotypic resistance was assessed among 92 HIV-1C-infected patients failing nevirapine and efavirenz-based regimens from a cohort of 552 Indian patients. Overall, prevalence of etravirine cross-resistance identified using the Tibotec Weighted Score was 41% (31.5% intermediately-resistant and 9.8% fully-resistant). The most frequently described nonnucleoside reverse transcriptase inhibitor-associated mutations included Y181 (35.9%), K101 (20.7%), G190 (17.4%), and V108 (15.2%). The resistant group demonstrated higher viral load (P = 0.01) and longer duration of antiretroviral treatment (P = 0.03) compared with the susceptible group.
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In this clinical trial, the late VF rate after successful suppression was very low. If achievable in routine clinical practice, virologic monitoring involving infrequent (e.g. annual) measurements might be considered; the implications of this for development of resistance need evaluating. Patients reporting missed doses early after ART initiation, despite achieving initial suppression, might require more frequent measurement and/or strategies for promoting adherence.
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Limited HIV-1 drug-resistance surveillance has been carried out in Ghana since the implementation of antiretroviral therapy (ART). This study sought to provide data on the profile of HIV-1 drug resistance in ART-experienced and newly diagnosed individuals in Ghana.
Cytochrome P450 (CYP) enzyme polymorphisms seem to significantly influence the variability of the responses to certain antiretroviral drugs and their toxicity levels. The objective of this study was to evaluate the influence of the CYP2B6 G516T polymorphism on hepatic, renal, immunological, and viral marker changes in HIV-1-positive patients receiving treatment in an ethnically diverse region of the Amazon.
In this study, a strong association of CYP2B6*6 and CYP2B6*18 alleles in relation to EFV and NVP plasma concentrations was found, which confirmed previous studies.
Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI), used for the treatment of human immunodeficiency virus (HIV)-1 infection. Approved by the US Food and Drug Administration in 1998, its indication was recently extended to include children as young as 3 months of age. The World Health Organization and many national guidelines consider efavirenz to be the preferred NNRTI for first-line treatment of children over the age of 3 years. Clinical outcomes of patients on three-drug antiretroviral regimens which include efavirenz are as good as or better than those for patients on all other currently approved HIV medications. Efavirenz is dosed once daily and has pediatric-friendly formulations. It is usually well tolerated, with central nervous system side effects being of greatest concern. Efavirenz increases the risk of neural tube defects in nonhuman primates and therefore its use during the first trimester of pregnancy is limited in some settings. With minimal interactions with antituberculous drugs, efavirenz is preferred for use among patients with HIV/tuberculosis coinfection. Efavirenz can be rendered inactive by a single point mutation in the reverse transcriptase enzyme. Newer NNRTI drugs such as etravirine, not yet approved for use in children under the age of 6 years, may maintain their activity following development of efavirenz resistance. This review highlights key points from the existing literature regarding the use of efavirenz in children and suggests directions for future investigation.
Administration of erlotinib with CYP3A4 inducers (dexamethasone) and inhibitors (ketoconazole and ritonavir) resulted in significant alterations in erlotinib exposure. Ketoconazole and ritonavir resulted in a 1.7- and 3.0-fold increase in erlotinib AUC, respectively, while dexamethasone results in a 0.6-fold decrease in erlotinib AUC. The CYP3A4 inducer efavirenz did not have a significant effect on erlotinib exposure.