Antiviral activity of low-dose alovudine in antiretroviral-experienced patients: results from a 4-week randomized, double-blind, placebo-controlled dose-ranging trial.
BACKGROUND
Alovudine inhibits replication of highly nucleoside reverse transcriptase inhibitor (NRTI)-resistant HIV strains in vitro. However, dose-dependent safety concerns resulted in its initial development being halted. Recently, a 4-week course of alovudine 7.5 mg/day added to a stavudine-free failing regimen yielded a significant decrease in viral load by -1.88 log(10) HIV-1 RNA copies/mL. The magnitude of the reduction in viral load suggested that lower doses might still be effective while offering adequate safety during long-term use.


OBJECTIVE
To determine whether lower dosages of alovudine still provide significant antiviral activity in patients with broad NRTI resistance.


METHODS
A randomized, double-blind, placebo-controlled trial investigating three doses of alovudine (0.5, 1 and 2 mg) or placebo added for 4 weeks to a failing regimen in patients with evidence of NRTI-resistant HIV strains [>or=2 thymidine-associated mutations (TAMs)]. The primary endpoint was the mean viral load reduction between baseline and week 4.


RESULTS
Seventy-two patients were enrolled in the study: 21, 13, 18 and 20 in the placebo and 0.5, 1 and 2 mg arms, respectively. Baseline median CD4 count and viral load were 298 cells/microL (range 44-692 cells/microL) and 3.9 log(10) copies/mL (range 2.5-5.2 log(10) copies/mL), respectively. Baseline viral isolates harboured a median of four TAMs. Alovudine was added to a median four-drug failing regimen. At week 4, compared with placebo, mean viral load changes were -0.42 log(10) [95% confidence interval (CI) -0.67 to -0.18] and -0.30 log(10) (-0.55 to -0.06) in the 2 and 1 mg arms, respectively. There was no significant change in CD4 cell count. Alovudine was well tolerated.


CONCLUSIONS
A 4-week course of alovudine 2 mg/day provided a modest but significant viral load reduction in patients harbouring viruses with a median of four TAMs.
Ghosn
J
J
Service des Maladies Infectieuses, Hôpital Pitié-Salpêtrière, Paris, France. jade.ghosn@psl.ap-hop-paris.fr
Quinson
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Sabo
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Cotte
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L
Piketty
C
C
Dorléacq
N
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Bravo
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ML
Mayers
D
D
Harmenberg
J
J
Mårdh
G
G
Valdez
H
H
Katlama
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C
D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects; D018791:CD4 Lymphocyte Count; D015224:Dideoxynucleosides / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D005260:Female; D006678:HIV / Q000235:genetics / Q000254:growth & development*; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D019562:Viral Load
D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D012367:RNA, Viral; C002854:alovudine