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)

The present study provides a characterization of the behavioral changes induced in preweaning mice by prenatal exposure to lamivudine (3TC), an antiviral drug recently entered in the clinical practice to treat HIV patients. Pregnant CD1 mice were given per os bidaily either 3TC at different doses (125, 250, or 500 mg/kg) or vehicle solution (saline 0.9%) from pregnancy day 10 to delivery. Data on reproductive performance, such as gestation length, litter size, and offspring viability, were collected. Offspring were then examined for a series of different somatic and behavioral end points, including sensorimotor development, ontogenetic pattern of ultrasonic vocalization, passive avoidance learning, and locomotor activity. In the absence of gross changes in somatic and sensorimotor development, a slight change in ultrasound emission was found on postnatal day (PND) 3, with 125 and 500 mg/kg 3TC-treated offspring emitting a lower number of ultrasounds. Learning and retention performances of a passive-avoidance task on PND 20-21 were unaffected by 3TC treatment, while decreased habituation in an automated locomotor activity test was evident in male offspring exposed to 250 and 500 mg/kg 3TC.
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PMID:Neurobehavioral effects of prenatal lamivudine (3TC) exposure in preweaning mice. 1044 Apr 80

Of all of the nucleoside inhibitors approved by the FDA for treatment of AIDS, (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC, lamivudine) is the only one with the unnatural (-)-beta-L configuration. The fluorinated derivative (-)-beta-2', 3'-dideoxy-5-fluoro-3'-thiacytidine [(-)-FTC] and its triphosphate form have also been reported to have excellent antiretroviral activity against HIV-1 reverse transcriptase (RT). Preliminary results of clinical trials suggest that (-)-FTC is 6- to 10-fold more potent than 3TC. However, the molecular mechanism for the observed enhanced clinical potency of (-)-FTC to inhibit viral replication is not understood. The present mechanistic studies used a transient kinetic approach and were designed to compare the incorporation of 3TC-TP and (-)-FTC-TP into DNA by HIV-1 RT and illuminate key features that may play a role in the differential potency. Here we show that (-)-FTC-TP is incorporated 10-fold more efficiently than 3TC-TP during HIV-1 RT-catalyzed RNA-dependent DNA synthesis. The enhanced incorporation efficiency of (-)-FTC-TP may be a key mechanistic feature that, in part, is responsible for the enhanced potency of (-)-FTC observed in ongoing clinical trials.
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PMID:Mechanistic studies show that (-)-FTC-TP is a better inhibitor of HIV-1 reverse transcriptase than 3TC-TP. 1046 41

An important component of triple-drug anti-AIDS therapy is 2', 3'-dideoxy-3'-thiacytidine (3TC, lamivudine). Single mutations at residue 184 of the reverse transcriptase (RT) in HIV cause high-level resistance to 3TC and contribute to the failure of anti-AIDS combination therapy. We have determined crystal structures of the 3TC-resistant mutant HIV-1 RT (M184I) in both the presence and absence of a DNA/DNA template-primer. In the absence of a DNA substrate, the wild-type and mutant structures are very similar. However, comparison of crystal structures of M184I mutant and wild-type HIV-1 RT with and without DNA reveals repositioning of the template-primer in the M184I/DNA binary complex and other smaller changes in residues in the dNTP-binding site. On the basis of these structural results, we developed a model that explains the ability of the 3TC-resistant mutant M184I to incorporate dNTPs but not the nucleotide analog 3TCTP. In this model, steric hindrance is expected for NRTIs with beta- or L- ring configurations, as with the enantiomer of 3TC that is used in therapy. Steric conflict between the oxathiolane ring of 3TCTP and the side chain of beta-branched amino acids (Val, Ile, Thr) at position 184 perturbs inhibitor binding, leading to a reduction in incorporation of the analog. The model can also explain the 3TC resistance of analogous hepatitis B polymerase mutants. Repositioning of the template-primer as observed in the binary complex (M184I/DNA) may also occur in the catalytic ternary complex (M184I/DNA/3TCTP) and contribute to 3TC resistance by interfering with the formation of a catalytically competent closed complex.
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PMID:Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with beta-branched amino acids. 1046 56

The emergence of genotypic resistance in protease and reverse transcriptase (RT) gene regions was longitudinally evaluated in plasma samples from a group of 12 HIV-1-infected patients treated with different combination of antiretroviral therapies and selected on the basis of their clinical failure. Complex mutational patterns in the reverse transcriptase gene were observed. In particular, combinations of AZT (41L, 67N, 70R, 210W, and 219Q/E) and 3TC (184M) were seen in 10 patients. Two patients presented codon 151 multinucleoside analogue resistance (MNR). Additionally, seven patients harbored RT nonnucleoside analogue-related resistance substitutions (98G, 103N, and 181C). Multiple protease-selected mutations were found in each patient with an average of six substitutions per patient, with 10I/F/V, 63P, 71V, 82A/T, 84V, and 90M being the most prevalent substitutions. Overall, these results showed that for most patients virological failure was coupled with detectable genotypic resistance. Furthermore, most patients exhibited genotypic resistance to almost all available anti-HIV-1 drugs. The high viral loads found in most patients at the end of the study suggest that the replication of these multidrug resistant viruses are not severely compromised. Phylogenetic analysis of these pol sequences revealed that a specific HIV-1 genotype prone to develop multidrug resistance was not found.
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PMID:Emergence and genetic evolution of HIV-1 variants with mutations conferring resistance to multiple reverse transcriptase and protease inhibitors. 1053 30

Efavirenz (SUSTIVA, DMP 266, EFV) is a novel non-nucleoside reverse transcriptase inhibitor, which shows good inhibitory activity against HIV-1. The pharmacokinetics of efavirenz allow for once daily dosing without regard to meals of normal composition. Efavirenz is a mild inducer of CYP 3A4. Clinically significant drug interactions have been reported with medications that are metabolised via the cytochrome P450 enzymes such as indinavir and saquinavir. Results from the studies collated for submission (003, 006, 020, 024 and ACTG 364) have demonstrated the potency and durability of once daily efavirenz in combination with zidovudine (AZT) + lamivudine (3TC), indinavir (IDV), nelfinavir (NFV), IDV + 2 NRTIs, and NFV + 2 NRTIs. Efavirenz was recently approved for commercial use in the USA and has received marketing authorisation in Europe and Canada.
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PMID:Clinical history of efavirenz. 1062 35

Study 006 is a pivotal Phase III, multicentre, randomized, open-label study designed to compare the antiretroviral activity and tolerability of efavirenz (EFV) + zidovudine (AZT) + lamivudine (3TC) with indinavir (IDV) + AZT + 3TC and EFV + IDV. Using both the 'observed data' analysis and intent-to-treat non-completer = failure analysis, the results at 48 weeks showed that efavirenz, in combination with AZT + 3TC was superior to IDV + AZT + 3TC. EFV + AZT + IDV was shown to be equally effective in patients with high and low baseline viral loads. Toxicities resulting in premature discontinuations were 3-fold higher in the IDV + AZT + 3TC arm than in both efavirenz-containing arms. Preliminary results suggested that efavirenz increased high density lipid (HDL) levels but the clinical significance of this observation is unknown. The results from Study 006 indicate that the combination EFV + AZT + 3TC is a highly active protease inhibitor-sparing regimen for first-line treatment of HIV-infected patients.
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PMID:Update on study 006--EFV + AZT + 3TC versus the current 'standard of care' IDV + AZT + 3TC. 1062 37

We describe a new human immunodeficiency virus type 1 (HIV-1) mutational pattern associated with phenotypic resistance to lamivudine (3TC) in the absence of the characteristic replacement of methionine by valine at position 184 (M184V) of reverse transcriptase. Combined genotypic and phenotypic analyses of clinical isolates revealed the presence of moderate levels of phenotypic resistance (between 4- and 50-fold) to 3TC in a subset of isolates that did not harbor the M184V mutation. Mutational cluster analysis and comparison with the phenotypic data revealed a significant correlation between moderate phenotypic 3TC resistance and an increased incidence of replacement of glutamic acid by aspartic acid or alanine and of valine by isoleucine at residues 44 and 118 of reverse transcriptase, respectively. This occurred predominantly in those isolates harboring zidovudine resistance-associated mutations (41L, 215Y). The requirement of the combination of mutations 41L and 215Y with mutations 44D and 44A and/or 118I for phenotypic 3TC resistance was confirmed by site-directed mutagenesis experiments. These data support the assumption that HIV-1 may have access to several different genetic pathways to escape drug pressure or that the increase in the frequency of particular mutations may affect susceptibility to drugs that have never been part of a particular regimen.
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PMID:A novel human immunodeficiency virus type 1 reverse transcriptase mutational pattern confers phenotypic lamivudine resistance in the absence of mutation 184V. 1068 19

Over the past decade, much progress has been made in understanding the risk factors and timing of perinatal HIV transmission. Even more impressive have been the successful clinical trials with antiretrovirals, such as ZDV, ZDV-3TC, and nevirapine, that demonstrated significant reductions in the risk for infant infection. Within the United States and Europe, these trial results have led to rapid implementation and dramatic decreases in new perinatal HIV cases since 1994. An immediate challenge is to rapidly translate the short-course antiretroviral trial results with ZDV and nevirapine into public health policy and practice in resource-poor settings, where almost 600,000 neonates continue to become infected by mother-infant HIV transmission each year. Physicians must also test strategies to further decrease the risk for infant HIV infection during the breast-feeding period.
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PMID:Update on perinatal HIV transmission. 1069 40

Although protease inhibitor (PI) therapy has improved the clinical status of patients with HIV infection, concerns have arisen that such treatment may have deleterious effects on glucose control, lipid metabolism, and body fat distribution. To determine whether initiation of PI therapy uniquely affects glucose and lipid metabolism, we analyzed paired data in HIV-infected patients before and after beginning antiretroviral therapy that included a PI (PI; N = 20) or lamivudine (3TC) but no PI (3TC; N = 9); and a control group on stable regimens that included neither of these agents (CONT: N = 12). Measurements included fasting glucose; insulin; triglycerides; total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol; HIV RNA; CD4+ lymphocytes; weight; and total and regional body composition. Neither weight nor total or regional fat content changed significantly in any group during the period of observation. Nonetheless, in patients beginning PI therapy, there were significant increases in glucose (+9+/-3 mg/dl; p = .0136), insulin (+12.2+/-4.9 U/ml; p = .023), triglycerides (+53+/-17 mg/dl; p = .0069), and total and LDL cholesterol (+32+/-11 and +18+/-5 mg/dl; p = .0082 and .0026, respectively). None of these parameters changed significantly in the 3TC or CONT groups. The PI and 3TC groups experienced comparable increases in CD4+ lymphocytes, suggesting that the observed metabolic effects may be associated with PIs uniquely, rather than improvement in clinical status. However, it is also possible that the metabolic effects of PIs are associated with more effective viral suppression, because a greater proportion of patients in the PI group achieved undetectable levels of virus. We conclude that changes in glucose and lipid metabolism are induced by PI therapy in the absence of significant changes in weight or fat distribution. Longer periods of follow-up will be required to determine the clinical significance of these changes. However, at the moment, the risks associated with these metabolic effects do not appear to outweigh improvements in survival seen with PI therapy.
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PMID:Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection. 1151 29

Administration of the combination of indinavir-zidovudine-lamivudine has been demonstrated to cause a large fraction of treated patients to have a decline in human immunodeficiency virus type 1 (HIV-1) copy number to below the detectability of sensitive assays. A recent investigation (G. L. Drusano, J. A. Bilello, D. S. Stein, M. Nessly, A. Meibohm, E. A. Emini, P. Deutsch, J. Condra, J. Chodakewitz, and D. J. Holder, J. Infect. Dis. 178:360-367, 1998) demonstrated that the durability of the antiviral effect was affected by combination chemotherapy. Zidovudine-lamivudine-indinavir differed significantly from the combination of zidovudine plus indinavir. We hypothesized that the addition of lamivudine might alter the regimen, producing a synergistic anti-HIV effect. In vitro analysis of drug interaction demonstrated that zidovudine-indinavir interacted additively. The addition of lamivudine in concentrations which suppressed viral replication by 20% or less by itself demonstrated marked increases in the synergy volume, increasing the synergy volume 20-fold with the addition of 320 nM lamivudine (which does not suppress HIV by itself) and 40-fold with the addition of 1,000 nM lamivudine (20% viral inhibition as a single agent). A fully parametric analysis with a newly developed model for three-drug interaction confirmed and extended these observations. The interaction term (alpha(IND,AZT, 3TC)) for all three drugs showed the greatest degree of synergy. This marked synergistic interaction among the three agents may explain some of the clinical results which differentiate this regimen from the double-drug regimen of zidovudine plus indinavir.
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PMID:The triple combination indinavir-zidovudine-lamivudine is highly synergistic. 1072 11


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