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: 4.48). 07/2005; 49(7):2828-33. DOI: 10.1128/AAC.49.7.2828-2833.2005
Source: PubMed


Racivir [RCV; (+/−)-β-2′,3′-dideoxy-5-fluoro-3′-thiacytidine], a 50:50 racemic mixture of the two β 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.

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    • "The RCV resistance profile is interesting; in fact, (−)FTC selects for M184V-resistant strains, while (+)FTC selects for T215Y-resistant strains [86]. Since the simultaneous selection of these two amino acid mutations is incompatible, such racemic mixture orthogonal resistance profile determines a delay in the onset of the drug resistance selection [87]. The long-term mitochondrial toxicity, however, is still to be fully assessed since (+)FTC triphosphate is only 36-fold selective for RT versus DNA polymerase γ [88]. "
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    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.
    Full-text · Article · Jun 2012
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    • "Its pharmacokinetic profile was excellent with a single dose per day. Racivir also showed promising antiviral activity in combination with d4T and efavirenz [25] . Elvucitabine (ACH-126, 443, L-d4FC, 2′-3′-didehydro-2′, 3′-dideoxy-β-L-5-fluorocytidine) is 10-to 20-fold superior to FTC for its anti-HIV-1 activity [26] . "
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