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Drug resistance is an increasing problem in the treatment of HIV infection. MIV-310 (alovudine), a nucleoside reverse transcriptase inhibitor, potently inhibits the replication of highly mutated strains of HIV in vitro. We examined the efficacy of MIV-310 in highly pretreated patients.In a phase II pilot study, 15 patients failing a current antiretroviral therapy with at least two thymidine-associated mutations (TAM) were given MIV-310 7.5 mg once daily for 4 weeks, in addition to their ongoing treatment. The primary endpoint was the plasma viral load reduction at week 4.At baseline, the median viral load was 3.93 log10 copies/ml and the median CD4 cell count was 360 cells/mm3. After 4 weeks of MIV-310 administration, the median decrease in viral load was −1.13 log10. Interestingly, the median reduction was only −0.57 log10 in the four patients on stavudine, contrasting with a median reduction of −1.88 log10 in the 11 patients not receiving concomitant stavudine. The viral load fell by a median of −1.60 log10 in patients with two to three TAM (n = 7), and by −1.88 log10 in patients with four or five TAM (n = 8). The viral load rebounded in all patients after MIV-310 cessation. No mutations were found in the reverse transcriptase coding region during MIV-310 treatment. MIV-310 was well tolerated, with no serious adverse events and no treatment withdrawals.MIV-310 7.5 mg/day efficiently reduced the HIV viral load in patients failing a multiple-drug regimen. Further studies with different dosages and longer administration times are urgently needed.