XI International HIV Drug Resistance Workshop: Basic Principles and Clinical Implications


Seville, Spain, 2–5 July 2002


IN VITRO EFFECTS OF MIV-310 (ALOVUDINE, 3´-FLUORODEOXY THYMIDINE, FLT) AGAINST HIV MUTANTS

Antivir Ther. 2002;7(Suppl 1):S18 (abstract no. 23)

L Vrang1, H Zhang1, S Palmer2, E-Y Kim3, T Merigan3 and B Oberg1,4
1Medivir, Huddinge, Sweden; 2HIV Drug Resistance Program, NCI-Fredrick, Md, USA; 3Center for AIDS Research, Stanford university, Calif., USA; and 4Karolinska Institute, Stockholm, Sweden

BACKGROUND: MIV-310 is a nucleoside analogue with structural similarities to zidovudine and with a potent inhibition of HIV in vitro. Early clinical trials in ARC/AIDS patients showed antiviral effect at daily doses of down to 2 mg. At that time no obvious advantage to zidovudine was observed and the development of MIV-310 was put on hold. Since then, multidrugresistant (MDR) HIV has appeared and an evaluation of MIV-310 against MDR HIV has been performed. A re-investigation of the safety of MIV-310 has removed an earlier misconception and revealed an adequate safety margin.

METHODS: Antiviral effects were determined in MT4-XTT based CPE assay and peripheral blood mononuclear cells (PBMCs) as ED50 values by recombinant HIV-1 isolates harbouring MDR and patient isolates. Selection of resistant virus was attempted by using MT-4 cells infected with HIV-1IIIB. Assays were also performed by use of antivirogram at Virco as described by Hertogs et al., Antimicrob Agents Chemother. 1998 Feb;42(2):269-76.

RESULTS: MIV-310 inhibits HIVIIIB at 0.008.0.021 μM, HIV wild-type clinic isolates at 0.0078.0.08 μM, Q151M containing MDR HIV-1 at 0.004.0.05 μM, viral variants with T69S+XX at 0.0036.0.53 μM, and a 67del (SG) mutant at 0.0047 μM. The most resistant mutant contained 35 reverse transcriptase (RT) mutations and had an IC50 of 0.53 μM in a T69S+XX genetic background. No resistance development was observed for HIV-1 grown in MT-4 cells after 49 passages in the presence of MIV-310.

CONCLUSION: A highly potent effect of MIV-310 was observed against most HIV mutants with resistance to other nucleoside analogues. This corresponds well to the lack of resistance development in cell culture where no resistance was observed in the pressure of MIV-310 under conditions when resistance developed in the presence of zidovudine, zalcitabine and lamivudine. The potent effect of MIV-310 against MDR has promoted a clinic trial in HIV patients failing present therapy.

PRESENTING AUTHOR: H Zhang

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