Article

Safety, pharmacokinetics, and efficacy of (+/-)-beta-2 ',3 '-dideoxy-5-fluoro-3 '-thiacytidine with efavirenz and stavudine in antiretroviral-naive human immunodeficiency virus-infected patients

Emory University, Atlanta, Georgia, United States
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.45). 07/2005; 49(7):2828-33. DOI: 10.1128/AAC.49.7.2828-2833.2005
Source: PubMed

ABSTRACT Racivir [RCV; (+/-)-beta-2',3'-dideoxy-5-fluoro-3'-thiacytidine], a 50:50 racemic mixture of the two beta nucleoside enantiomers, is currently in development for the treatment of human immunodeficiency virus type 1 (HIV-1) infections. RCV was administered once a day orally for 14 days at doses of 200, 400, or 600 mg in combination with stavudine and efavirenz to HIV-1-infected treatment-naïve male volunteers in a phase Ib/IIa study. Six volunteers at each dose were monitored for a total of 35 days for tolerance, pharmacokinetics, and plasma HIV RNA levels. RCV in combination with stavudine and efavirenz was well tolerated at all doses tested. Pharmacokinetic parameters were dose proportional, and the maximum concentration of drug in serum at all doses exceeded the 90% effective concentration for wild-type HIV-1. Viral loads dropped as expected in all dosage groups, with mean reductions from 1.13 to 1.42 log10 by day 4 and 2.02 to 2.43 log10 by day 14. HIV RNA levels remained suppressed for more than 2 weeks in the absence of any additional therapy, with mean viral loads ranging from 2.1 to 2.6 log10 below baseline through day 28. By day 35, HIV RNA levels began to increase but still remained >1 log10 below baseline levels.

0 Bookmarks
 · 
74 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Resistance to human immunodeficiency virus type 1 (HIV-1) represents a significant problem in the design of novel therapeutics and the management of treatment regimens in infected persons. Resistance profiles can be elucidated by defining modifications to the viral genome conferred upon exposure to novel nucleoside reverse transcriptase (RT) inhibitors (NRTI). In vitro testing of HIV-1LAI-infected primary human lymphocytes treated with β-D-2',3'-dideoxy-2',3'-didehydro-5-fluorocytidine (DFC; Dexelvucitabine; Reverset) produced a novel deletion of AGT at codon 68 (S68Δ) alone and in combination with K65R that differentially affects drug response. Dual-approach clone techniques utilizing TOPO cloning and pyrosequencing confirmed the novel S68Δ in the HIV-1 genome. The S68Δ HIV-1 RT was phenotyped against various antiviral agents in a heteropolymeric DNA polymerase assay and in human lymphocytes. Drug susceptibility results indicate that the S68Δ displayed a 10- to 30-fold increase in resistance to DFC, lamivudine, emtricitabine, tenofovir, abacavir, and amdoxovir and modest resistance to stavudine, β-d-2',3'-oxa-5-fluorocytidine, or 9-(β-D-1,3-dioxolan-4-yl)guanine and remained susceptible to 3'-azido-3'-deoxythymidine, 2',3'-dideoxyinosine (ddI), 1-(β-D-dioxolane)thymine (DOT) and lopinavir. Modeling revealed a central role for S68 in affecting conformation of the β3-β4 finger region and provides a rational for the selective resistance. These data indicate that the novel S68Δ is a previously unrecognized deletion that may represent an important factor in NRTI multidrug resistance treatment strategies.
    Antimicrobial Agents and Chemotherapy 02/2011; 55(5):2054-60. DOI:10.1128/AAC.01700-10 · 4.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Twenty-five years ago, nucleoside analog 3′-azidothymidine (AZT) was shown to efficiently block the replication of HIV in cell culture. Subsequent studies demonstrated that AZT acts via the selective inhibition of HIV reverse transcriptase (RT) by its triphosphate metabolite. These discoveries have established the first class of antiretroviral agents: nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs). Over the years that followed, NRTIs evolved into the main component of antiretroviral drug combinations that are now used for the treatment of all populations of HIV infected patients. A total of thirteen NRTI drug products are now available for clinical application: eight individual NRTIs, four fixed-dose combinations of two or three NRTIs, and one complete fixed-dose regimen containing two NRTIs and one non-nucleoside RT inhibitor. Multiple NRTIs or their prodrugs are in various stages of clinical development and new potent NRTIs are still being identified through drug discovery efforts. This article will review basic principles of the in vitro and in vivo pharmacology of NRTIs, discuss their clinical use including limitations associated with long-term NRTI therapy, and describe newly identified NRTIs with promising pharmacological profiles highlighting those in the development pipeline.This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, volume 85, issue 1, 2010.
    Antiviral Research 01/2009; 85(1):39-58. DOI:10.1016/j.antiviral.2009.09.014 · 3.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: During the retrotranscription process, characteristic of all retroviruses, the viral ssRNA genome is converted into integration-competent dsDNA. This process is accomplished by the virus-coded reverse transcriptase (RT) protein, which is a primary target in the current treatments for HIV-1 infection. In particular, in the approved therapeutic regimens two classes of drugs target RT, namely, nucleoside RT inhibitors (NRTIs) and nonnucleoside RT inhibitors (NNRTIs). Both classes inhibit the RT-associated polymerase activity: the NRTIs compete with the natural dNTP substrate and act as chain terminators, while the NNRTIs bind to an allosteric pocket and inhibit polymerization noncompetitively. In addition to these two classes, other RT inhibitors (RTIs) that target RT by distinct mechanisms have been identified and are currently under development. These include translocation-defective RTIs, delayed chain terminators RTIs, lethal mutagenesis RTIs, dinucleotide tetraphosphates, nucleotide-competing RTIs, pyrophosphate analogs, RT-associated RNase H function inhibitors, and dual activities inhibitors. This paper describes the HIV-1 RT function and molecular structure, illustrates the currently approved RTIs, and focuses on the mechanisms of action of the newer classes of RTIs.
    06/2012; 2012:586401. DOI:10.1155/2012/586401
    This article is viewable in ResearchGate's enriched format

Full-text (2 Sources)

Download
9 Downloads
Available from
Jun 5, 2014