Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Efavirenz (EFV) is metabolized by cytochrome P450 2B6 (CYP2B6) in the liver. We analyzed the genotypes of CYP2B6 and their contribution to plasma EFV concentrations in 35 EFV-treated patients in International Medical Center of Japan. The mean plasma EFV concentration of patients with CYP2B6 *6/*6 (Q172H and K262R) (25.4+/-7.5 microM, +/-SD, n = 2) was significantly higher than that of patients with genotypes *6 heterozygote (9.9+/-3.3 microM, n = 10) or without alleles *6 (8.0+/-2.6 microM, n = 23) (p < 0.0001). To confirm our result, we further analyzed nine patients (three with high EFV concentrations and arbitrarily selected six with normal EFV concentrations) treated in Osaka National Hospital, and it resulted that the only three patients with the high concentrations were the *6/*6 holder. EFV dose could be decreased in those patients harboring the genotype to reduce toxicity with compromising potency, representing the first step of the Tailor-Made therapy of HIV-1 infection.
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PMID:Homozygous CYP2B6 *6 (Q172H and K262R) correlates with high plasma efavirenz concentrations in HIV-1 patients treated with standard efavirenz-containing regimens. 1519 12

The specificity of nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) for the RT of human immunodeficiency virus type 1 (HIV-1) has prevented the use of simian immunodeficiency virus (SIV) in the study of NNRTIs and NNRTI-based highly active antiretroviral therapy. However, a SIV-HIV-1 chimera (RT-SHIV), in which the RT from SIVmac239 was replaced with the RT-encoding region from HIV-1, is susceptible to NNRTIs and is infectious to rhesus macaques. We have evaluated the antiviral activity of efavirenz against RT-SHIV and the emergence of efavirenz-resistant mutants in vitro and in vivo. RT-SHIV was susceptible to efavirenz with a mean effective concentration of 5.9 +/- 4.5 nM, and RT-SHIV variants selected with efavirenz in cell culture displayed 600-fold-reduced susceptibility. The efavirenz-resistant mutants of RT-SHIV had mutations in RT similar to those of HIV-1 variants that were selected under similar conditions. Efavirenz monotherapy of RT-SHIV-infected macaques produced a 1.82-log-unit decrease in plasma viral-RNA levels after 1 week. The virus load rebounded within 3 weeks in one treated animal and more slowly in a second animal. Virus isolated from these two animals contained the K103N and Y188C or Y188L mutations. The RT-SHIV-rhesus macaque model may prove useful for studies of antiretroviral drug combinations that include efavirenz.
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PMID:Efavirenz therapy in rhesus macaques infected with a chimera of simian immunodeficiency virus containing reverse transcriptase from human immunodeficiency virus type 1. 1532 15

Forty-nine AIDS patients, most of who were antiretroviral therapy (ARV) naive, with active tuberculosis, were treated with Rifampin 600 mg, Isoniazid 400 mg and Pirazinamide 2 g daily. They also received ARV, consisting of Efavirenz (600 mg/day) plus 2 NRTIs. All patients were prospectively followed for at least 24 months. Baselines were: male/female ratio 2:1, mean age 34.7 +/- 9.4 yrs; weight 51 +/- 9.0 kg, viral load 5.6 +/- 0.6 logs, CD4 cell count 101 +/- 128 cells/ mm3. Follow up mean values of data logs of VL and CD4+ cell /mm3 counts were: VL 1.7 and CD4+ 265; VL 1.3 and CD4+ 251; VL 1.4 and CD4+ 326 at 6, 12 and 24 months, respectively. Weight gain changes were: 5 +/- 9.9 +/- 12 and 21 +/- 16 kg respectively at 6, 12 and 24 months. A non-concomitant ARV regimen was introduced at least three weeks after TB treatment initiation. Severe adverse reactions included rash (two), toxic hepatitis (six), Immune Reconstitution Syndrome (seven), and four deaths. We conclude that Efavirenz at a daily dose of 600 mg is sufficient and safe to treat HIV/TB patients using a Rifampin containing regimen.
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PMID:Efficacy and safety of Efavirenz in HIV patients on Rifampin for tuberculosis. 1547 53

Efavirenz (Sustiva), Bristol-Myers Squibb) is a non-nucleoside reverse transcriptase inhibitor that has been used successfully since the late 1990s to treat HIV-1 infection, and has since become a cornerstone of antiretroviral therapy. The efficacy and potency of efavirenz has been established in many clinical trials and cohort studies, where it has been compared with unboosted or ritonavir (Norvir, Abbott Laboratories Ltd)-boosted protease inhibitors, nevirapine (Viramune, Boehringer Ingelheim Ltd); and three nucleoside analog-based regimens. Pharmacokinetics allowing for a convenient once-daily administration make efavirenz one of the first agents to be included in once-daily regimens. Tolerability of efavirenz is satisfactory, although CNS-related toxicity can occur, and is still poorly understood. New insights into the pharmacokinetics of efavirenz could help to manage this unwanted toxicity. This drug profile will examine the principal data concerning the efficacy, pharmacokinetics and safety that have made efavirenz a standard of care in HIV-1 therapy, and will comment on new data that could change the way efavirenz is used in the near future.
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PMID:Efavirenz for HIV-1 infection in adults: an overview. 1548 31

Efavirenz treatment has been associated with increases in HDL-cholesterol concentrations, and the circulating levels of the drug have been related to the multidrug resistance gene 1 (MDR-1) C3435T polymorphism. The changes in the measured lipid parameters were evaluated in 59 HIV-infected patients initiating efavirenz-based treatment at baseline and at 12 months of follow-up. Efavirenz treatment increased HDL-cholesterol. The changes in concentrations appeared to be influenced by the MDR-1 gene polymorphism, in which CC > CT > TT.
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PMID:The efavirenz-induced increase in HDL-cholesterol is influenced by the multidrug resistance gene 1 C3435T polymorphism. 1571 46

Efavirenz and nevirapine are frequently used drugs in antiretroviral therapy. Rashes are common side effects of these drugs. In this study, we examined the characteristics of efavirenz- and nevirapine-associated rashes. This prospective nonrandomized multicenter study included 662 HIV-infected patients (efavirenz: 325, nevirapine: 337) to determine incidence, duration, cross-reactivity, and outcome upon reexposure. Of the treated patients, 4.5% (n=30) developed rashes (nevirapine: 2.4% and efavirenz: 6.4%). In four patients treatment was not interrupted. Three patients were re-exposed to the initial drug without any side effects. Therapy with nevirapine or efavirenz does not have to be interrupted if rashes exhibit no blistering, mucosal manifestations, or systemic signs.
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PMID:[Rashes in HIV-infected patients undergoing therapy with nevirapine or efavirenz]. 1572 99

Efavirenz has now become commonly used to treat HIV infection. Neuropsychiatric disorders have been reported in patients treated with efavirenz. Several factors often make it hard to determine the cause of these disorders: HIV infected patients take many different drugs, they may suffer from various organ diseases, and may also be heavily affected by problems in their everyday life. The French experts group working on neuropsychiatric side effects of efavirenz has undertaken a review of these disorders with the aim to identify: (1) semiology, (2) epidemiology in the global population, in HIV infected patients, and in patients treated with efavirenz. The expert group suggests recommendations to manage these disorders.
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PMID:[Neurospychiatric symptoms in HIV infected patients and the role of efavirenz]. 1574 68

Full quantum mechanical computational study has been carried out to study binding of efavirenz (EFZ), a second generation FDA approved nonnucleoside inhibitor, to HIV-1 reverse transcriptase (RT) and its K103N and Y181C mutants using the MFCC (molecular fractionation with conjugate caps) method. The binding interaction energies between EFZ and each protein fragment are calculated using a combination of HF/3-21G, B3LYP/6-31G* and MP2/6-31G* ab initio levels. The present computation shows that Efavirenz binds to HIV-1 RT predominantly through strong electrostatic interaction with the Lys101 residue. The small loss of binding to K103N mutant by Efavirenz can be attributed to a slightly weakened attractive interaction between the drug and Lys101 due to a conformational change of mutation. The small loss of binding to Y181C mutant by efavirenz can be attributed to the Glu698 residue moving closer to EFZ due to conformational change, which results in an increase of repulsive energy relative to the wild type (WT). The binding of efavirenz-derived DPC961 to HIV-1 RT is enhanced by an additional attractive interaction to residue Hid235 and reduced repulsion to Glu698, resulting in an increase of binding energy by about 4 kcal/mol.
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PMID:Quantum study of mutational effect in binding of efavirenz to HIV-1 RT. 1578 28

We have modeled highly active antiretroviral therapy (HAART) for AIDS in rhesus macaques infected with a chimera (RT-SHIV) of simian immunodeficiency virus containing reverse transcriptase from human immunodeficiency virus type-1 (HIV-1). Seven RT-SHIV-infected macaques were treated with a combination of efavirenz (200 mg orally once daily), lamivudine (8 mg/kg subcutaneously once daily), and tenofovir (30 mg/kg subcutaneously once daily). Plasma viral RNA levels in all animals were reduced by more than 1,000-fold after 4 weeks and, in six of the seven animals, were reduced to undetectable levels after 10 weeks. Virus loads increased slightly between 12 and 16 weeks of treatment, associated with problems with the administration of efavirenz. After a change in the method of efavirenz administration, virus loads declined again and remained undetectable in the majority of animals for the duration of therapy. Treatment was stopped for three animals after 36 weeks of therapy, and virus loads increased rapidly. Posttreatment RT-SHIV isolates had no mutations associated with resistance to any of the three drugs. Efavirenz treatment was stopped, but lamivudine and tenofovir treatment for two other macaques was continued. The virus load in one of these two animals rebounded; virus from this animal was initially free of drug-resistance mutations but acquired the K65R mutation in reverse transcriptase at 11 weeks after efavirenz treatment was withdrawn. These results mimic HAART of HIV-1-infected humans. The RT-SHIV/rhesus macaque model should be useful for studies of tissue reservoirs and sites of residual replication that are not possible or practical with humans.
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PMID:Suppression of virus load by highly active antiretroviral therapy in rhesus macaques infected with a recombinant simian immunodeficiency virus containing reverse transcriptase from human immunodeficiency virus type 1. 1591 89

In order to evaluate the properties of several HIV-1 reverse transcripase(RT) inhibitors, Efavirenz (SUSTIVA) and a set of its derivatives (benzoxazinones) have been placed into the nonnucleoside analogue binding site of the enzyme by molecular docking. The resulting geometries were used for a molecular dynamics simulation and binding energy calculations. The enzyme-inhibitor binding energies were estimated from experimental inhibitory activities (IC90). The correlation of the predicted and experimental binding energies were satisfactory acceptable as indicated by r2 = 0.865. Based on MD simulations, the obtained results indicate that the tight association of the ligand to the HIV-1 RT binding pocket was based on hydrogen bonding between Efavirenz's N1 and the oxygen of the backbone of Lys 101, with an estimated average distance of 1.88 A. Moreover, electrostatic interaction was mainly contributed by two amino acid residues in the binding site; Lys 101 and His 235. MD simulations open the possibility to study the reaction of the flexible enzyme to those substances as well as the overall affinity.
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PMID:Molecular mechanics PBSA ligand binding energy and interaction of Efavirenz derivatives with HIV-1 reverse transcriptase. 1596 17


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