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)

To develop an animal model for the therapy of AIDS with human immunodeficiency virus type 1 (HIV-1)-specific reverse transcriptase (RT) inhibitors, we recently constructed a hybrid simian immunodeficiency virus (SIV)/HIV-1 in which the RT gene of SIV was replaced by the RT gene of HIV-1. This chimaeric virus, designated RT-SHIV, was found to be markedly sensitive to the inhibitory effects of both nucleoside (ddN) and non-nucleoside RT inhibitors (NNRTIs). In contrast, SIV was inhibited only by ddNs (i.e., 3TC and AZT), but not NNRTIs. When RT-SHIV was grown in the presence of 3TC, nevirapine, TSAO-m3T or the thiocarboxanilide UC-42 drug-resistant mutant virus strains emerged in cell culture as rapid as for HIV-1(IIIB). The antiviral sensitivity/resistance spectrum of the mutant RT-SHIV strains against NNRTIs and ddNs, and the nature of the mutations that appeared in their RT were similar to those of the mutant HIV-1 strains that were selected under identical experimental conditions. Infection of macaques with RT-SHIV may be a useful tool for studying the mechanism of NNRTI-resistance development and the therapy of NNRTI-resistant viruses in an animal model.
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PMID:Sensitivity/resistance profile of a simian immunodeficiency virus containing the reverse transcriptase gene of human immunodeficiency virus type 1 (HIV-1) toward the HIV-1-specific non-nucleoside reverse transcriptase inhibitors. 754 Dec

HIV causes chronic infection and is associated with persistent viral replication and a high viral mutation rate. It is an illusion to think that monotherapy with any antiretroviral agent will have a major and lasting impact on this disease. Monotherapy with antitubercular agents led to dramatic improvements in treatment, but the development of drug resistance meant that these improvements were of only short duration, and hence it was concluded that drugs should be combined. The response to the limited efficacy of nucleoside analogue monotherapy in HIV infection has in many instances been the stance that 'currently available antiretrovirals are no good; it is better not to treat'. In addition, regulatory insistence on clinical end-points has also hampered antiretroviral drug development. It is implied that antiretrovirals must be tested in populations with fairly advanced HIV infection, in whom the least success may be expected. The regulatory bind has also resulted in artificial and counterproductive treatment guidelines. Common sense and experience in infectious diseases dictate that treatment should hit hard and early. No study published thus far undermines the concept that early therapy is better than late therapy or that a tolerable combination of drugs with additive or synergistic anti-HIV activity is better than nucleoside monotherapy. Promising data have been generated in trials on combinations of zidovudine plus didanosine or zalcitabine; a combination of zidovudine and lamivudine (3TC) may be even more promising.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Combination antiretroviral therapy. Back to the future. 761

3TC (GR109714X) is a cytidine dideoxynucleoside analogue which has been shown to have in vitro activity against a variety of strains of HIV-1 and is currently being investigated in clinical trials as a treatment for HIV infection. An HPLC method for the determination of 3TC in human urine has been developed and validated. The method allows direct injection of urine (10 microliters) using HPLC column switching followed by UV detection. On-line extraction is performed using a Spherisorb-SCX (5 microns, 20 x 4.0 mm) eluted with deionized water at 1 ml min-1. 3TC is retained while the bulk of urine constituents are eluted to waste. The SCX column is then backflushed to a BDS-Hypersil-C18 (5 microns, 250 x 4.6 mm) and eluted with 100 mM acetate pH 4.5-methanol (95:5, v/v) for final separation. 3TC is detected by UV absorbance at lambda = 285. The quantitation range of the assay was 0.5-500 micrograms ml-1. The method has demonstrated sufficient ruggedness to be used in support of 3TC clinical trials. Application to other cytidine analogues including DDC has been demonstrated.
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PMID:Determination of 2'-deoxy-3'-thiacytidine (3TC) in human urine by liquid chromatography: direct injection with column switching. 800 52

Human Immunodeficiency Virus replication offers several targets for inhibitory compounds, the foremost presently being the HIV reverse transcriptase. Since the beginning of the epidemic three nucleoside analogue drugs--Zidovudine, Didanosine and Zalcitabine--which act at the reverse transcriptase enzyme are already licensed for use in AIDS-therapy, and others--Stavudine, Alovudine and Lamivudine--are still under clinical evaluation. Although there is a very significant research work for newer drugs for HIV-therapy, it seems that for the next future Zidovudine will remain the most important drug of antiretroviral therapy.
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PMID:[Future possibilities of drug therapy of acquired immunodeficiency syndrome]. 801 18

The effects of (+)-beta-D-dioxolane-cytosine ((+)-D-beta-DOC), (-)-beta-L-dioxolane-cytosine ((-)-L-beta-DOC), (+)-beta-D-oxathiolane-cytosine ((+)-D-beta-OTC), (-)-beta-L-oxathiolane-cytosine ((-)-L-beta-OTC, or 3TC), 3'-azido-2',3'-dideoxy-5-methyl-cytidine (5-Me-AZDC), and 3'-azido-2',3'-dideoxyuridine (AZDU) on Epstein-Barr virus (EBV) DNA replication in vitro were tested in P3HR-1 cells. Two anti-EBV drugs, 3'-azido-3'-deoxythymidine (AZT) and 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG, or ganciclovir), were used as positive controls. The inhibitory effects on EBV DNA synthesis were quantified by membrane filter and Southern blot hybridizations with an EBV-specific probe BamHI-W fragment. The 50% effective doses (ED50) for EBV DNA replication were 0.15, 0.83, 1.5, 8.3, 14, and 7.7 microM for DHPG, (-)-L-beta-DOC, (+)-D-beta-DOC, (+)-D-beta-OTC, (-)-L-beta-OTC, and AZT, respectively. In contrast, 5-Me-AZDC and AZDU were not effective at concentrations as high as 30 microM. These results indicated that both (-)-L-beta-DOC and (+)-D-beta-DOC were more potent than AZT, which has previously been shown to have anti-EBV activity. (-)-L-beta-DOC and (+)-D-beta-DOC have also been previously demonstrated to suppress the infectivity of human immunodeficiency virus type 1 (HIV-1). Thus, (-)-L-beta-DOC represents the first nucleoside analog with L-configuration exhibiting significant antiviral activities against both EBV and HIV.
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PMID:Some nucleoside analogs with anti-human immunodeficiency virus activity inhibit replication of Epstein-Barr virus. 858 56

We recently found that phosphatidyl-2',3'-dideoxycytidine (phosphatidyl-ddC) had substantial anti-hepatitis B virus (HBV) activity in vitro compared to 2',3'-dideoxycytidine (ddC) (Hostetler et al. (1994) Antiviral Res. 24, 59-67). Upon administration of liposomal phosphatidyl-ddC to mice, a 40-fold higher drug area under curve was observed in the liver. To evaluate the possibility of using liver-targeted anti-HBV nucleosides to treat woodchuck hepatitis virus, we wanted to find the most potent and selective lipid conjugates. It has been shown that 2',3'-dideoxy-3'-thiacytidine as a racemic mixture of the cis-isomer (cis-(+/-)-BCH-189) has much greater activity against HBV viruses than ddC in vitro. Recently, it was shown that the (-)-beta-L-enantiomer (3TC) is more active and less toxic than the (+)-beta-D-form ((+)-BCH-189). To determine whether phospholipid conjugates of 3TC retain antiviral activity in 2.2.15 cells as demonstrated previously with ddC, we synthesized the 1,2-dipalmitoyl-sn-glycerol-3-phosphate conjugates of (+/-)-BCH-189 and 3TC and assessed their anti-HBV and anti-HIV activities, in vitro. Phosphatidyl-3TC and phosphatidyl-BCH-189 had antiviral activity comparable to the respective free drugs in 2.2.15 cells which chronically produce HBV. In HIV-1-infected human peripheral blood mononuclear cells and HT4-6C cells, phosphatidyl-3TC and phosphatidyl-(+/-)-BCH-189 exhibited significantly lower activity than the corresponding free nucleosides. In view of the documented ability of phosphatidyl-ddC to target drug to the liver, it seems reasonable to expect that phosphatidyl-3TC or phosphatidyl-(+/-)-BCH-189 could be employed to provide greatly enhanced hepatic antiviral activity in HBV infection in vivo.
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PMID:Phosphatidyl-2',3'-dideoxy-3'-thiacytidine: synthesis and antiviral activity in hepatitis B-and HIV-1-infected cells. 858 65

We attempted to determine whether HIV-1 developed resistance to (--)-2',3'-dideoxy-3'-thiacytidine ((--)-3TC or 3TC, lamivudine) in patients with advanced human immunodeficiency virus type 1 (HIV-1) infection during therapy with 3TC. Genotypic analysis of HIV-1 strains isolated from 6 patients receiving 3TC revealed that as early as 2 months of therapy, HIV-1 developed a Met to Val amino acid substitution at codon 184 (Met184-->Val) in the reverse transcriptase-coding region of the pol gene. A detailed study of a series of HIV-1 strains isolated from a patient demonstrated that Met at codon 184 was first substituted with Ile by 2 weeks of 3TC therapy, followed by the substitution with Val by 8 weeks. All HIV-1 strains with the Met184-->Val substitution were profoundly less susceptible to 3TC (1800- to 5500-fold decreased sensitivity) as compared to pretherapy virus strains. These strains were also moderately less sensitive to 2',3'-dideoxycytidine (4.5- to 9-fold), but more sensitive to 3'-azido-2',3'-dideoxythymidine (2- to 14-fold). A decrease in viremia levels and an increase in CD4 counts were observed early in therapy; however, these changes were only transient. Our data suggest that reversal of such beneficial changes is associated with the Met184-->Val substitution of the pol gene of HIV-1. The data also suggest that 3TC, as a single agent, may induce virologic and immunologic improvement in patients with advanced HIV-1 infection, but only transiently.
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PMID:Genotypic and phenotypic characterization of HIV-1 isolated from patients receiving (--)-2',3'-dideoxy-3'-thiacytidine. 858 67

The traditional approach of assessing new treatments in clinical end-point studies is becoming less viable for ethical and practical reasons. As more antiretroviral options become available and as treatment is commenced at earlier, asymptomatic stages of infection, alternative methods of assessing the efficacy of antiretroviral regimens are necessary. Recently developed quantitative measures of viral nucleic acids are already proving invaluable in predicting which drugs and combinations are most promising for further investigation. These approaches have been used to evaluate the effect of antiretroviral drugs in clinical trials comparing zidovudine (AZT) monotherapy with combinations of AZT/didanosine (ddI), AZT/zalcitabine (ddC), and AZT/lamivudine (3TC). In one study (Trial BW 34,225-02), levels of HIV-1 RNA in serum fell by approximately 50% in antiretroviral-naive patients on commencement of AZT monotherapy. For patients treated with AZT/ddI and AZT/ddC, reductions in serum HIV-1 RNA levels were significantly greater (80-90%). Increases in CD4 cell count corresponded with these decreases with the decrease in viral load. A second study (Trial NUCB3001) comparing the effect of AZT monotherapy with AZT/3TC therapy in antiretroviral-naive individuals showed even more marked and sustained superiority of the combination regimen over monotherapy (>1.8 log RNA copies/ml vs. 0.7 log RNA copies/ml after 4 weeks). These studies showed that the reduction in viral load achieved with combination therapies were greater and were sustained for longer periods than with monotherapy. The most pronounced effect was achieved by the AZT/3TC combination. Assessment of viral load is a practical and promising approach to monitoring antiretroviral action.
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PMID:Measuring viral load in the clinical setting. 859 6

It has become apparent that the beneficial effects of zidovudine (AZT) and other antivirals will not continue indefinitely. However, synergistic activity of lamivudine (3TC) in combination with AZT, as well as reversal of phenotypic AZT resistance due to the presence of 3TC resistance-inducing mutations, has been documented in vitro. Two trials (NUCB 3001 and NUCB 3002) are therefore investigating the potential of the combination of 3TC with AZT. HIV-1-positive patients with CD4 cell counts of 100-400 cells/mm3 who had not previously received AZT were enrolled into study NUCB 3001 and treated with either AZT (200 mg t.i.d.) or 3TC (300 mg b.i.d.) plus AZT (200 mg t.i.d.) for 24 weeks. Open-label treatment with the combination regimen was offered for an additional 24 weeks. Both treatment groups experienced an initial increase in CD4 cell count. This increase was significantly greater and more sustained in the combination treatment group than in those receiving AZT monotherapy. Participants originally receiving AZT monotherapy, who changed to combination therapy after 24 weeks, experienced a rise in CD4 count. Those who began the study receiving combination therapy maintained their increased CD4 count for the duration of the study. A statistically significant difference in CD4 cell count between the two treatment groups was observed over the entire 48-week treatment period (p </= 0.0001) indicating that initial combination therapy was superior to monotherapy followed by a switch combination therapy after 24 weeks. Both treatment groups experienced a reduction in HIV-RNA levels and cellular viraemia, but these reductions were significantly greater in the combination treatment group than in those receiving AZT monotherapy. In addition, among patients initially randomized to AZT monotherapy, a significant reduction in the viral RNA concentration was observed after switching to combination therapy at week 24. There was an 80% reduction in p24 antigen levels from baseline in the combination treatment group compared with a 34% reduction from the baseline in the AZT monotherapy group, at 24 weeks. HIV-1-positive patients with CD4 cell counts of 100-400 cells/mm3 who had previously received a minimum of 24 weeks AZT treatment were enrolled into study NUCB 3002 and received either AZT monotherapy (200 mg t.i.d. plus placebo); AZT (200 mg t.i.d.) plus 3TC (300 mg b.i.d.) or AZT (200 mg t.i.d.) plus 3TC (150 mg b.i.d.) for 24 weeks. Open-label treatment with 3TC plus optional AZT was offered for a further 24 weeks (open-label phase). The study is still ongoing, but an initial increase in CD4 cell count was observed in the combination groups whereas, in the AZT monotherapy group, no discernible increase in CD4 cell count was observed at any time. The favorable effect of combination treatment with AZT and 3TC on CD4 cell count persisted throughout the open-label phase of the study. The addition of 3TC to the treatment regimens of patients who initially received AZT monotherapy had a favorable effect on CD4 cell count. Combination treatment with 3TC and AZT also resulted in a significantly greater reduction in viral load compared with AZT monotherapy. In conclusion, combination therapy with AZT plus 3TC produces beneficial effects on CD4 cell counts, HIV-1 RNA levels, and p24 antigen levels, which appear to be greater and more sustained than those produced by AZT monotherapy or any combination therapy to date. This combination appears to offer increased efficacy compared with AZT monotherapy without an increased risk of adverse experiences. Future studies to identify those patients most likely to benefit from such treatment and the optimum time for its initiation are therefore warranted.
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PMID:Zidovudine and lamivudine: results of phase III studies. 859 10

The US Food and Drug Administration (FDA) has approved the marketing of five new drugs for treatment of HIV infection. Stavudine (D4T; Zerit -- Bristol-Myers Squibb) and lamivudine (3TC; Epivir -- Glaxo Wellcome) are nucleoside analogs similar to zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC). Saquinavir (Invirase -- Roche), ritonavir (Norvir -- Abbott) and indinavir (Crixivan -- Merck) are protease inhibitors, a new class of anti-HIV drugs.
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PMID:New drugs for HIV infection. 860 77


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