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)

Patients with HIV infection manifest increased T lymphocyte apoptosis. This study investigated the influence of antiretroviral therapy (ART) upon lymphocyte apoptosis in 23 HIV-infected adults naive to protease inhibitors. Patients were enrolled in a treatment trial consisting of Nelfinavir (NFV), d4T, or NFV + d4T for 24 weeks, followed by triple therapy (NFV + reverse transcriptase inhibitors) for an additional 24 weeks. Spontaneous T cell apoptosis in cultured PBMC decreased by 23.67 +/- 18.2% (P < 0.006) at 48 weeks and plasma HIV RNA decreased by 1.79 +/- 0.59 log(10) RNA copies/ml (P < 0.001). The absolute decrease and slope of T cell apoptosis correlated with plasma virus load and with activated CD8 T cells and was inversely correlated with CD4 T cells. We conclude that reduction in chronic antigenic stimulation and the absence of cellular signals elicited by viral products contribute to the rescue of T lymphocytes from apoptosis, which facilitates immunologic recovery in ART-treated patients.
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PMID:Reduction in T cell apoptosis in patients with HIV disease following antiretroviral therapy. 1049 8

A series of new substituted-aryl phosphoramidate derivatives of the anti-HIV drug d4T were synthesized as membrane-soluble nucleotide prodrugs, to extend and quantify the SAR observed for an earlier series of related derivatives. All of the compounds were found to be significantly more potent against HIV in cell culture than the nucleoside analogue d4T, and most were also found to be significantly more potent than the parent phosphoramidate. A Hansch type QSAR analysis was applied to the combined series of 21 compounds. The results of this analysis revealed anti-HIV activity to be principally dependent on lipophilicity in a quadratic manner, with terms representing substituent steric bulk and electronic effects having a minimal significance.
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PMID:Design and synthesis of lipophilic phosphoramidate d4T-MP prodrugs expressing high potency against HIV in cell culture: structural determinants for in vitro activity and QSAR. 1051 82

This study evaluated the influence of zidovudine (ZDV) resistance mutations on the antiviral effect of the combination of stavudine (D4T) plus didanosine (ddI) in patients treated previously with ZDV plus zalcitabine (ddC). Twenty patients who had been treated with ZDV plus ddC for a median duration of 11 months (range, 7-42 months) were switched to D4T (40 mg twice a day [BID]) + ddI (200 mg BID) in an open pilot study lasting 6 months. The CDC classes were A (n = 10) and B (n = 10). The median baseline CD4 count was 285/mm(3) and the median baseline plasma virus RNA (Amplicor HIV Monitor RT-PCR assay) was 4.6 log copies/ml. Population-based sequence analysis detected mutations associated with resistance to reverse transcriptase (RT) inhibitors in the RT domain of virus RNA from baseline plasma samples in 13/20 (65%) patients. Twelve patients had mutations associated with zidovudine resistance (3 T215Y - M41L - L210W; 3 T215Y - M41L; 2 T215Y - L210W; 3 T215Y; 1 K70R) and 1 patient had a multi-dideoxynucleoside resistance mutation (QI5IM). Patients with a resistance mutation had a significantly lower RNA suppression after 3 and 6 months (median RNA reduction -0.5 log and -0.1 log) than the remaining patients (-1.6 log and -2 log). Fifty percent of patients with wild-type viruses had undetectable plasma RNA after 24 weeks of D4T plus ddI therapy, whereas all those with mutated viruses had HIV RNA concentration > 3 log copies/ml at week 24 (P <.05). Our finding may have implications when deciding on a second line therapy with three or four drugs that includes two new nucleoside analogues. Cross-resistance between nucleoside analogues deserves maximal attention to ensure optimal antiretroviral therapy and design algorithms for antiretroviral management based on genotypic antiretroviral resistance testing.
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PMID:Mutations conferring resistance to zidovudine diminish the antiviral effect of stavudine plus didanosine. 1053 34

An effective synthesis of thymogen was developed. Conjugates of 2',3'-didehydro-3'-deoxythymidine (nucleoside d4T) with thymogen were prepared in which the nucleoside hydroxyl group was linked to the thymogen carboxyl group of either tryprophan or glutamic acid residues. It was shown that the anti-HIV activity of the d4T-thymogene conjugate with the tryptophan linkage was comparable to that of d4T, whereas its cytotoxicity was nil. The d4T-tryptophan conjugate also displayed high anti-HIV activity.
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PMID:[Conjugates of 2',3'-didehydro-3'-deoxythymidine with thymogen. Synthesis and anti-HIV activity]. 1056 2

In an attempt to combine the anti-HIV-inhibitory capacity of nucleoside reverse transcriptase (RT) inhibitors (NRTI) and non-nucleoside RT inhibitors (NNRTI), several heterodimer analogues of the previously reported [AZT]-(CH(2))(3)-[TSAO-T] prototype have been prepared. In these novel series, other NRTIs, an expanded range of linkers with different conformational freedom and other attachment sites for these linkers on the base part of the NRTI analogue have been explored. Moreover, in order to circumvent the dependence of the NRTI moiety of the heterodimer on activation by cellular nucleoside kinases, novel heterodimers in which the NRTI is bearing a masked monophosphate group at the 5'-position are described. Among the novel heterodimers, several derivatives show a potent anti-HIV-1 activity, which proved comparable, or even superior, to that of the AZT heterodimer prototype. The nature of the NRTI was important for the eventual anti-HIV-1 activity. In particular, the d4T heterodimer derivative containing a propyl linker between the N-3 positions of the base of TSAO-T and d4T was approximately 5- to 10-fold more inhibitory to HIV-1 than the corresponding AZT heterodimer prototype.
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PMID:Potential multifunctional inhibitors of HIV-1 reverse transcriptase. Novel [AZT]-[TSAO-T] and [d4T]-[TSAO-T] heterodimers modified in the linker and in the dideoxynucleoside region. 1060 4

Among the clinically used nucleoside analogue inhibitors that target human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), there is little detailed mechanistic information on the interactions of 2',3'-didehydro-2', 3'-dideoxythymidine-5'-triphosphate (d4TTP) with the enzyme. primer-template complex and how these interactions compare with those of the natural substrate, dTTP. Using a pre-steady-state kinetic analysis, we found that d4TTP was incorporated by HIV-1 RT just as efficiently as dTTP during both DNA- and RNA-dependent DNA synthesis. To our knowledge, these results represent the first observation of a 3'-modified nucleoside triphosphate analogue that has an incorporation efficiency comparable to that observed for the natural substrate during DNA synthesis by HIV-1 RT. This information provides a mechanistic basis for understanding the inhibition of HIV-1 RT by d4TTP as well as insight into the clinically observed lack of d4T resistance mutations in HIV-1 RT isolated from AIDS patients.
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PMID:Mechanism of inhibition of the human immunodeficiency virus type 1 reverse transcriptase by d4TTP: an equivalent incorporation efficiency relative to the natural substrate dTTP. 1060 55

The dNN study evaluated the safety, efficacy and pharmacokinetic interactions of the combination of stavudine (2',3'-didehydro-2',3'-dideoxythymidine; D4T), nelfinavir and nevirapine in 25 HIV-infected subjects who received treatment for up to 29 weeks. This brief report presents the study design and preliminary data.
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PMID:dNN study: stavudine, nelfinavir and nevirapine. Preliminary safety, activity and pharmacokinetic interactions. 1072 13

Initial studies of multiple-agent antiretroviral combinations including the thymidine nucleoside analogue reverse transcriptase inhibitor (RTI) stavudine (2',3'-didehydro-2',3'-dideoxythymidine; D4T) have shown potent anti-HIV effects in both treatment-naive and -experienced patients. A number of ongoing randomized comparative trials are assessing stavudine-based multiple agent combinations, including protease inhibitor-containing and -sparing regimens, triple nucleoside RTI regimens and regimens including non-nucleoside RTIs and/or hydroxyurea as initial or subsequent therapy. Results of these studies should help to define additional first-line treatment options and strategies for sequencing antiretroviral treatment regimens.
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PMID:Stavudine-based multiple agent combinations: initial studies and ongoing comparative trials. 1072 16

The reduction in the efficacy of rescue treatment (administered on a clinical basis) due to drug resistance was retrospectively quantified in 55 human immunodeficiency virus type 1 (HIV-1)-infected patients failing highly active antiretroviral therapy (HAART) by using a novel score calculation system based upon HIV-1 reverse transcriptase (RT) and protease (PR) mutations. Patients were all naive for nelfinavir (NFV) and efavirenz (EFV) and were assigned to one of the following rescue therapy schedules: (i) 17 patients received NFV + EFV + stavudine (d4T) (group A); (ii) 14 patients received NFV + saquinavir (SQV) + lamivudine (3TC) + d4T/zidovudine (AZT) (group B); (iii) 19 patients received NFV + d4T + didanosine (ddI)/3TC/zalcitabine (ddC) (group C); (iv) five patients received miscellaneous treatments including NFV (group D). Responders were considered patients showing a drop in HIV-1 RNA level > 0.5 log10 after 3 months of therapy. Forty-eight (28 responders and 20 non-responders) out of 55 patients completed the first 3 months of rescue therapy and reduction in HIV-1 viral load was found to be significantly higher in group A compared to groups B and C (81.2% responders vs. 38.5 and 40.0%, respectively). At baseline, no patient carried EFV- or d4T-resistant HIV-1 strains, despite prolonged administration of d4T, while 41/48 (87.2%) patients had mutations conferring resistance to NFV in the absence of previous treatment with this drug. A significant inverse correlation between reduction in viral load and reduction in therapy efficacy due to drug resistance, as determined by the score calculation system, was found (r = 0.62). A cut-off value of 36% reduction in therapy efficacy showed a positive predictive value (capacity to detect failure of rescue treatment) of 81.2% and a negative predictive value (ability to detect successful treatment) of 75.8%. In addition, 45 out of 48 patients completed also the 9-12 month period of rescue therapy and 10/28 responders had a rebound in HIV-1 viral load level detected after the first 3 months of rescue therapy. Of these, 5/7 (71.4%) showed a further reduction in rescue therapy efficacy due to the emergence of new mutations.
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PMID:Quantification of the impact of HIV-1 reverse transcriptase and protease mutations on the efficacy of rescue HAART. 1080 19

The distribution of currently available anti-HIV drugs into the CNS is reviewed with a focus on transport mechanisms. Among these drugs, nucleoside analogs are most well studied for their CNS distribution. The average reported values of the CSF/plasma steady-state concentration or corresponding AUC ratios are 0.23 (AZT), 0.06 (ddI), 0.04 (ddC), 0.49 (d4T), and 0.08 (3TC). Active efflux transport out of the CNS appears to be a predominant mechanism limiting nucleoside access to the CNS, although poor penetration may contribute to some extent for some polar nucleosides. The nature of the efflux pump for these drugs is speculated to be MRP-like transporter(s) in blood-brain and blood-CSF barriers. For non-nucleoside and protease inhibitors, much research remains to be done on the extent, time course, and mechanisms of their CNS distribution. The CNS penetration of some protease inhibitors is restricted by P-glycoprotein. A better understanding of transport mechanisms of anti-HIV drugs in the CNS is essential to develop approaches to enhance CNS delivery of available drugs and to identify new drugs less subject to active efflux transporter(s) in the CNS.
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PMID:Investigation of distribution, transport and uptake of anti-HIV drugs to the central nervous system. 1083 65


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