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 emergence of mutations encoding drug resistance is supposed to be a significant limitation to the clinical efficacy of inhibitor compounds directed against specific HIV-1 enzymatic targets. We have used a commercial test (Visible Genetics Inc., Paris, France) to study the prevalence of mutations occurred in HIV-1 protease and reverse transcriptase (RT) genes in 93 HIV-1 infected patients treated with at least one regimen containing a protease inhibitor (PI) and failing to the current therapeutic regimen. Protease mutations conferring resistance to at least one PI were detected in 46/93 (49.4%) of strains, 25 (26.8%) of which showed resistance to all PIs. Reverse transcriptase mutations conferring resistance to at least one RT inhibitor were detected in 57/93 (61.2%) of strains, 18 (19.3%) of which showed resistance to all RT inhibitors. The most frequent RT mutations were T215Y/F, M41L, and M184V (41.9, 40.8, and 40.8%, respectively), while L63P, L10R/V, and A71V/T (58, 41.9, and 34.4%, respectively) were the most represented protease substitutions. We have found no mutations encoding for multiple dideoxynucleoside resistance (Q151M or T69SS). Twelve of our patients (12.9%) had no mutation encoding drug resistance and were completely sensitive to all RT and protease inhibitors. Therefore, not all virological failures are caused by HIV-1 genomic resistance.
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PMID:Analysis of HIV-1 mutation patterns in patients failing antiretroviral therapy. 1117 Feb 34

This open-label, multicenter, single-arm clinical trial assessed the 48-week efficacy of a twice-daily triple nucleoside reverse-transcriptase inhibitor regimen containing a lamivudine (150 mg)-zidovudine (300 mg) combination tablet (COM) and abacavir (ABC; 300 mg) in 87 antiretroviral therapy-experienced, protease inhibitor-naive patients infected with human immunodeficiency virus type 1 (HIV-1). At baseline, the median plasma HIV-1 RNA level was 3.10 log(10) copies/mL, and the median CD4 cell count was 506 cells/mm(3). An intent-to-treat&rcolon;observed analysis showed that, at weeks 24 and 48 of treatment, HIV-1 RNA level was <400 copies/mL in 48 (76%) of 63 and 45 (82%) of 55 patients, respectively, and <50 copies/mL in 37 (59%) of 63 and 31 (56%) of 55 patients, respectively. Previous zidovudine or lamivudine use and presence at baseline of the M184V reverse-transcriptase mutation did not impact virologic response. Median CD4 cell counts were maintained above baseline throughout the study. COM plus ABC was generally well tolerated.
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PMID:Twice-daily triple nucleoside intensification treatment with lamivudine-zidovudine plus abacavir sustains suppression of human immunodeficiency virus type 1: results of the TARGET Study. 1117 Sep 82

Protease genotype, as a variable in outcome to combination therapy for human immunodeficiency virus (HIV) type 1 infection, was evaluated among protease inhibitor-naive children and adolescents who had received extensive treatment with reverse-transcriptase inhibitors. After 24 weeks of combination therapy, 35% had viral and immune success (VSIS patients), 19% had viral and immune failure (VFIF patients), and 46% had viral failure but marked improvement in CD4 T cells (VFIS patients). Disease stage was the only pretherapy clinical variable associated with outcome (P=.02). Although reverse-transcriptase genotype was unrelated to outcome, pretherapy protease genotype was related significantly to therapy response (P=.005). Odds for immune or viral failure were 17.7 to 1 and 2.5 to 1, respectively, for protease genotype as a single variable. Protease genotype combined with disease stage and CD4 cell percentage predicted correct therapy response for 81% of patients (100% of VFIF, 78% of VSIS, and 75% of VFIS patiens). Naturally occurring amino acid polymorphisms in protease provide sensitive biomarkers for treatment response among inhibitor-naive patients with advanced HIV disease.
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PMID:Human immunodeficiency virus type 1 protease genotype predicts immune and viral responses to combination therapy with protease inhibitors (PIs) in PI-naive patients. 1117 Sep 83

The feasibility of providing postexposure prophylaxis (PEP) after sexual or injection drug use exposures to human immunodeficiency virus (HIV) was evaluated. PEP was provided within 72 h to individuals with exposures from partners known to have or to be at risk for HIV infection. PEP consisted of 4 weeks of antiretroviral medications and individually tailored risk-reduction and medication-adherence counseling. Among 401 participants seeking PEP, sexual exposures were most common (94%; n=375). Among sexual exposures, receptive (40%) and insertive (27%) anal intercourse were the most common sexual acts. The median time from exposure to treatment was 33 h. Ninety-seven percent of participants were treated exclusively with dual reverse-transcriptase inhibitors, and 78% completed the 4-week treatment. Six months after the exposure, no participant developed HIV antibodies, although a second PEP course for a subsequent exposure was provided to 12%. PEP, after nonoccupational HIV exposure, is feasible for persons at risk for HIV infection.
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PMID:Feasibility of postexposure prophylaxis (PEP) against human immunodeficiency virus infection after sexual or injection drug use exposure: the San Francisco PEP Study. 1118 Nov 46

Evidence suggests that nevirapine, a non-nucleoside reverse-transcriptase inhibitor, might be very effective in the prevention of HIV-1 integration and the reduction of risk of HIV-1 acquisition after exposure. We used a triple combination regimen, including nevirapine, for prophylaxis after occupational or sexual exposure to HIV-1 infection. Of 57 individuals who started therapy, only 41 returned for follow-up. Five had a grade three or four drug-induced hepatitis, two of whom also had a rash. This high rate of major adverse events raises concerns over the safety of such a regimen for its use in this population.
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PMID:Prophylaxis with a nevirapine-containing triple regimen after exposure to HIV-1. 1151 14

DPC 961 and DPC 083 are investigational non-nucleoside reversed transcriptase inhibitors (NNRTI) being evaluated for the treatment of HIV infections (Corbett et al., Antimicrob Agents Chemother 1999;43:2893-2897). Both compounds are chiral and are synthesized as single enantiomers by an asymmetric synthetic pathway (Magnus et al., Tetrahedron Lett 2000;41:3015-3019). A chiral method was developed to control the enantiomeric purity of the drug substance and to monitor for any chiral inversion in the drug substance and in the tablet formulation during stability studies. Three columns were evaluated: Chiralpak AD, Chirobiotic V, and Whelk-O. All three columns have broad applicability and can resolve enantiomers of compounds of very diverse molecular structure and polarity. The three columns were evaluated with various mobile phase compositions for their ability to resolve the racemic mixtures of DPC 083, DPC 961, and their respective enantiomers and for their selectivity toward the synthetic impurities of the two drug substances. Nonaqueous mobile phases were selected because the two drugs are poorly water soluble. The separation between the unwanted enantiomer of DPC 083 and DPC 961, which is a major impurity of DPC 083, in particular, was closely monitored. The final method was fully validated and is used for the routine testing of the drug substance and tablets.
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PMID:Column selection and method development for the determination of the enantiomeric purity of investigational non-nucleoside reverse transcriptase inhibitors. 1128 24

We have tested for combined anti-HIV-1 effects of a hammerhead ribozyme and antiretroviral drugs and the possibility of reducing the drug burden of patients on highly active antiretroviral therapy (HAART). The antiretroviral compounds used represent the three groups in HAART: nucleoside analogue reverse-transcriptase inhibitors, nonnucleoside reverse-transcriptase inhibitors, and protease inhibitors. A human T cell line (HUT78), stably expressing a hammerhead ribozyme targeted to nef (hhRz.nef(9016-9029)), was infected with HIV-1(SF2) in the presence of a single drug. The combined effects on HIV-1 replication were measured by p24 antigen determinations over a 2-week period. In the presence of the ribozyme, smaller amounts of antiretroviral drugs were required to reduce the HIV-1 p24 levels equally as much as when only drugs were present. The results support a strategy of combining ribozyme gene therapy with HAART to improve the long-term outcome of anti-HIV-1 therapy.
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PMID:Smaller amounts of antiretroviral drugs are needed when combined with an active ribozyme against HIV-1. 1131 14

We investigated whether or not mutations at codon 215 in the HIV reverse-transcriptase-encoding gene predicted a lower efficacy of didanosine therapy, as defined by survival of patients and change in CD4 cell counts in 121 HIV-infected, zidovudine-experienced patients. A trend for shorter survival, although not reaching significance, was observed for patients with HIV strains with the reverse transcriptase codon 215 mutation (P = 0.07), but this trend disappeared after adjustment for initial CD4 cell counts. During the first 3 months on didanosine therapy, the increase in CD4 cell counts was greater in patients who were wild type at codon 215 than in those with the mutation at codon 215 (P = 0.03). These data suggest that there was a better initial CD4 response to didanosine therapy in patients with HIV without the mutation at codon 215, but that this response did not translate into increased survival.
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PMID:Predictive value of codon 215 reverse transcriptase mutation on the efficacy of didanosine in HIV-infected, zidovudine-experienced patients. 1132 50

The Inter-Company Collaboration for AIDS Drug Development (ICC) is now enrolling for its first series of clinical trials for HIV infection for patients with CD4 (T-helper) counts between 200 and 500, who have not previously taken AZT. Each 48-week trial will assign 75 volunteers to three different treatment arms. In the first trial (ICC 001), everyone will receive AZT (Retrovir) and ddC (HIVID). As the third drug, one group will receive nevirapine (an experimental non-nucleoside reverse-transcriptase inhibitor); another group will receive saquinavir (Indirase); and the third treatment group will receive the placebo. In the second trial (ICC 002), everyone will receive AZT and ddI. One group will receive nevirapine as the third drug; another group will receive 3TC as the third drug. For information on how to enroll, volunteers may call the coordinating center at PAREXEL International Corporation (800-925-AIDS). Or volunteers can call directly to the office of the physician in their city (listed in the article).
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PMID:ICC Trials -- first study enrolling. 1136 34

Researchers are investigating aspects of the life cycle of HIV that can be exploited by new drugs. Promising compounds include those that block the fusion of HIV to cells; dextran sulfate is an example of such a drug. Reverse transcriptase inhibitors continue to receive attention, with the focus placed on dealing with the resistance that HIV develops to this class of drugs. Other studies are targeting HIV integrase, an enzyme that integrates HIV genetic material into the host cell's DNA, as the next important target of antiretroviral therapy. Two zinc finger inhibitors are currently in clinical trials, one of which is about to enter phase I/II dose-ranging studies. Finally, several novel protease inhibitors are in development. Pharmacia and Upjohn are developing a protease inhibitor that is relatively easy to make and is active against HIV.
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PMID:New wave antiretrovirals. 1136 38


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