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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antiretroviral monotherapy for initial drug characterization risks the selection of resistant virus, yet monotherapy is the only setting where many fundamental properties of a new drug can be reliably determined. Using data on viral replication kinetics and dynamics, we designed an accelerated (14 day) open-label study of single agent emtricitabine (formerly known as FTC)--a nucleoside reverse transcriptase inhibitor--to select a dosing regimen for further therapeutic study. Five regimens (25 mg bd, 100 mg od, 200 mg od, 100 mg bd and 200 mg bd) were evaluated in HIV-1-infected subjects over a 14 day dosing period to determine the optimal dose and pharmacokinetics. Serial blood samples for virological, pharmacokinetic and intracellular FTC-triphosphate measurements were drawn frequently. A dose-response relationship for the antiviral activity of emtricitabine was established, with total daily doses of 200 mg or more producing the greatest median HIV-1 viral load suppression: 1.72-1.92 log10. Based on virological outcomes, dose-response analysis and intracellular triphosphate levels, a once-daily dose of 200 mg was selected for further long-term clinical study. Adverse events possibly related to emtricitabine were unremarkable. The antiviral activity of emtricitabine correlated well with intracellular FTC-triphosphate concentrations. This study design is a safe, useful tool for early dose selection for drugs with potent antiretroviral activity and linear pharmacokinetics.
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PMID:Prototype trial design for rapid dose selection of antiretroviral drugs: an example using emtricitabine (Coviracil). 1158 Dec 29

A growing concern in the pursuit of new therapies for HIV-1 infection is the potential for the virus to develop drug resistance. With the advent of modern antiretroviral therapy and the common use of combined modalities, it is difficult to identify in the clinic the mutations associated with a specific drug. In general, drug selection of mutants using a relevant cell system, such as primary human lymphocytes, is a good prognosticator of what will happen in humans. In this study, HIV-infected human peripheral blood mononuclear cells were exposed, at a concentration of 1- to 10-fold the median effective antiviral concentration, to the nucleosides (-)-beta-2',3'-dideoxy-3'-thia-5-fluorocytidine [(-)-FTC] (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC), 3'-azido-2',3'-dideoxyuridine (CS-87, AZDU), 3'-azido-2',3'-dideoxy-5-methylcytidine (CS-92, AZMC), 2',3'-didehydro-3'-deoxythymidine (d4T), beta-L-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine (beta-L-D4FC), beta-L-2',3'-dideoxyadenine SATE[beta-L-ddAMP-bis(tbutylSATE)], beta-L-5-fluoro-2',3'-dideoxycytidine (L-FddC), and the protease inhibitors nelfinavir and amprenavir (VX-478). Virus from the culture supernatant was amplified by PCR and analysed by both HIV-1 reverse transcriptase and protease line probe assay. All the L-nucleoside analogues tested selected for the V184 mutation, including the L-pyrimidine nucleosides 3TC (-)-FTC, beta- L-FddC, beta-L-D4FC and the beta-L-purine nucleoside. beta-L-D4FC also selected for K/R65 in addition to V184, indicating that these two mutations are linked and compatible in vitro. No pattern of mutations leading to resistance or reduced susceptibility was discerned with d4T. Rapid genotyping analysis revealed the different kinetics and mutations obtained by in vitro selection in HIV-infected cells exposed to nucleoside analogues and protease inhibitors.
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PMID:Early detection of mixed mutations selected by antiretroviral agents in HIV-infected primary human lymphocytes. 1159 90

Drug-resistant mutants with a methionine-to-valine substitution at position 184 of reverse transcriptase (M184V) emerged within 5 weeks of initiation of therapy in four newborn macaques infected with simian immunodeficiency virus (SIVmac251) and treated with lamivudine (3TC) or emtricitabine [(-)-FTC] (two animals per drug). Thus, this animal model mimics the rapid emergence of M184V mutants of HIV-1 during 3TC therapy of human patients. One animal of each treatment group developed fatal immunodeficiency at 12 weeks of age, which is similar to the rapid disease course seen in most untreated SIVmac251-infected infant macaques. To further evaluate the effect of the M184V mutation on viral fitness and virulence, groups of juvenile macaques were inoculated with the molecular clone SIVmac239 with either the wild-type sequence (group A [n = 5]) or the M184V sequence (SIVmac239-184V; group B [n = 5] and group C [n = 2]). The two SIVmac239-184V-infected animals of group C did not receive any drug treatment, and in both animals the virus population reverted to predominantly wild type (184M) by 8 weeks after inoculation. The other five SIVmac239-184V-infected animals (group B) were treated with (-)-FTC to prevent reversion. Although virus levels 1 week after inoculation were lower in the SIVmac239-184V-infected macaques than in the SIVmac239-infected animals, no significant differences were observed from week 2 onwards. Two animals in each group developed AIDS and were euthanized, while all other animals were clinically stable at 46 weeks of infection. These data demonstrate that the M184V mutation in SIV conferred a slightly reduced fitness but did not affect disease outcome.
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PMID:Virulence and reduced fitness of simian immunodeficiency virus with the M184V mutation in reverse transcriptase. 1202 41

Both the beta-D-(+) and beta-L-(-)-enantiomers of 2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine (D4FC) are clinically relevant compounds because of their potent anti-HIV and anti-HBV activities. Cross-resistance to L-D4FC with HBV containing a mutation in the conserved polymerase YMDD region has been observed. In order to better understand the effects of stereochemistry on planar 5-fluorinated cytidine analogs and to gain insight into resistance caused by YMDD mutations in HIV-1 reverse transcriptase (RT), a combination of transient kinetic studies and computer modeling were employed. In contrast to studies with the (+) and (-) isomers of 3TC-TP and FTC-TP, it was found that wild type RT had a high enantiomeric selectivity between the D-(+) and L-(-) isomers of D4FC-TP. While no resistance was conferred by the methionine 184 to valine mutation to D-D4FC-TP, L-D4FC-TP was incorporated 50- to 70-fold less efficiently. The kinetic parameters of incorporation in the presence of L-D4FC-TP by RT(WT) and the mechanism of resistance by RT(M184V) were found to be distinct from those seen with the corresponding L-isomers containing an oxathiolane ring: (-)-3TC-TP and (-)-FTC-TP. Molecular modeling suggests that L- and D-D4FC-TP are positioned in the active site favorably for incorporation by RT(WT) and that L-D4FC-TP, but not D-D4FC-TP, is sterically hindered by the addition of a beta branched amino acid at position 184 of RT(M184V).
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PMID:Interactions of enantiomers of 2',3'-didehydro-2',3'-dideoxy-fluorocytidine with wild type and M184V mutant HIV-1 reverse transcriptase. 1240 4

The methionine-to-valine mutation in codon 184 (M184V) in reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) or simian immunodeficiency virus (SIV) confers resistance to (-)-2'-deoxy-3'-thiacytidine (3TC; lamivudine) and increased sensitivity to 9-[2-(phosphonomethoxy)propyl]adenine (PMPA; tenofovir). We have used the SIV model to evaluate the effect of the M184V mutation on the emergence of resistance to the combination of 3TC plus PMPA. A site-directed mutant of SIVmac239 containing M184V (SIVmac239-184V) was used to select for resistance to both 3TC and PMPA by serial passage in the presence of increasing concentrations of both drugs. Under these selection conditions, the M184V mutation reverted in the majority of the selections. Variants resistant to both drugs were found to have the lysine-to-arginine mutation at codon 65 (K65R), which has previously been associated with resistance to PMPA in both SIV and HIV. Similarly, in rhesus macaques infected with SIVmac239-184V for 46 weeks and treated daily with (-)-2'-deoxy-5-fluoro-3'-thiacytidine [(-)-FTC], there was no reversion of M184V, but this mutation reverted to 184 M in all three animals within 24 weeks of treatment with (-)-FTC and PMPA. Although the addition of PMPA to the (-)-FTC therapy induced a decrease in virus loads in plasma, these loads eventually returned to pre-PMPA levels in each case. All animals receiving this combination developed the K65R mutation. These results demonstrate that the combination of PMPA with 3TC or (-)-FTC selects for the K65R mutation and against the M184V mutation in SIV RT.
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PMID:Reversion of the M184V mutation in simian immunodeficiency virus reverse transcriptase is selected by tenofovir, even in the presence of lamivudine. 1250 28

The most significant new information about anti-HIV drugs offered in Barcelona concerned those drugs that are either already available or which will soon be available. This includes new information about T-20 (now called enfuvirtide or Fuzeon) and atazanavir--two drugs which will likely be approved within the next six months. Another new drug likely to be approved soon is FTC (Coviracil), a close relative of 3TC (lamivudine, Epivir), though its importance is less certain than that of enfuvirtide and atazanavir. Important new information was also released about tenofovir (Viread), a drug approved by the FDA late in 2001. Equally important were new observations about some older drugs, particularly the combination of ddI and d4T. Many comparative studies of different drug combinations were also reported, offering new information about the relative value of a number of treatment strategies.
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PMID:Anti-HIV drug updates--three drugs on the near horizon. 1264 72

Despite the availability of 16 antiretroviral drugs approved for the treatment of HIV infection, current combination regimens present challenges. Newer antiretroviral drugs are needed to improve convenience, reduce toxicity and, of particular importance, to provide antiretroviral activity against viral strains resistant to the currently available antiretroviral agents. Candidate drugs with novel properties are in development in the two currently available drug classes: HIV reverse transcriptase inhibitors (nucleoside analogs, non-nucleoside analogs and nucleotide analogs) and HIV protease inhibitors (PI). Investigational nucleoside analog reverse transcriptase inhibitors (nRTI) include emtricitabine (FTC) and amdoxovir (DAPD), and investigational non-nucleoside reverse transcriptase inhibitors (NNRTI) include DPC 083 and TMC 125. New protease inhibitors under investigation include atazanavir (BMS-232 632), tipranavir, and TMC 114. In addition, newer agents with novel mechanisms of action such as HIV entry inhibitors (that inhibit the three steps of HIV entry: CD4 attachment, chemokine receptor binding and membrane fusion) and HIV integrase inhibitors are under investigation. Investigational entry inhibitors include PRO 542 (a CD4 attachment inhibitor), Schering C (a chemokine receptor inhibitor), enfuvirtide (T-20) and T-1249, inhibitors of membrane fusion. Investigational HIV integrase inhibitors include S-1360. Continued progress in the treatment of HIV disease will result from the development of new antiretroviral drugs.
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PMID:New antiretroviral drugs. 1266 50

Beta-D and beta-L-enantiomers of 2',3'-dideoxycytidine analogues are potent chain-terminators and antimetabolites for viral and cellular replication. Seemingly small modifications markedly alter their antiviral and toxicity patterns. This review discusses previously published and recently obtained data on the effects of 5- and 2'-fluorine substitution on the pre-steady state incorporation of 2'-deoxycytidine-5'-monophosphate analogues by HIV-1 reverse transcriptase (RT) in light of their biological activity. The addition of fluorine at the 5-position of the pyrimidine ring altered the kinetic parameters for all nucleotides tested. Only the 5-fluorine substitution of the clinically relevant nucleosides (-)-beta-L-2',3'-dideoxy-3'-thia-5-fluorocytidine (L-FTC, Emtriva), and (+)-beta-D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine (D-D4FC, Reverset), caused a higher overall efficiency of nucleotide incorporation during both DNA- and RNA-directed synthesis. Enhanced incorporation by RT may in part explain the potency of these nucleosides against HIV-1. In other cases, a lack of correlation between RT incorporation in enzymatic assays and antiviral activity in cell culture illustrates the importance of other cellular factors in defining antiviral potency. The substitution of fluorine at the 2' position of the deoxyribose ring negatively affects incorporation by RT indicating the steric gate of RT can detect electrostatic perturbations. Intriguing results pertaining to drug resistance have led to a better understanding of HIV-1 RT resistance mechanisms. These insights serve as a basis for understanding the mechanism of action for nucleoside analogues and, coupled with studies on other key enzymes, may lead to the more effective use of fluorine to enhance the potency and selectivity of antiviral agents.
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PMID:Probing the mechanistic consequences of 5-fluorine substitution on cytidine nucleotide analogue incorporation by HIV-1 reverse transcriptase. 1452 28

The Food and Drug Administration has approved Emtriva (FTC, emtricitabine), a new nucleoside reverse transcriptase inhibitor to be used in combination with other antiretroviral agents for the treatment of patients with HIV infection.
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PMID:FDA notifications. NRTI Emtriva receives FDA approval. 1468 1

The FDA approved FTC (emtricitabine, Emtriva) in July 2003 for use by adults in combination with other anti-HIV drugs. FTC is a nucleoside analog reverse transcriptase inhibitor (NRTI). Other drugs in this class include 3TC, abacavir, AZT, Combivir, d4T, d4T XR, ddC, ddI, ddI EC and Trizivir.
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PMID:FTC (emtricitabine, Emtriva). 1469 67


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