Antiviral activity and tolerability of amdoxovir with zidovudine in a randomized double-blind placebo-controlled study in HIV-1-infected individuals.
BACKGROUND
Amdoxovir acts synergistically with zidovudine in vitro and the combination prevents or delays the selection of thymidine analogue and K65R mutations. In silico studies have shown that a reduced dose of zidovudine (200 mg) results in decreased zidovudine-monophosphate levels, associated with toxicity, while maintaining zidovudine-triphosphate levels, which are associated with antiviral effects. Here, we aimed to assess the short-term tolerability and antiviral activity of amdoxovir in combination with reduced and standard doses of zidovudine.


METHODS
The study was a double-blind, placebo-controlled study in HIV-1-infected patients not receiving antiretroviral therapy and with plasma HIV-1 RNA > or =5,000 copies/ml. Patients were randomized to 10 days of twice-daily treatment with 200 mg zidovudine, 300 mg zidovudine, 500 mg amdoxovir, 500 mg amdoxovir plus 200 mg zidovudine or 500 mg amdoxovir plus 300 mg zidovudine. The mean change in viral load (VL) log(10) and area under the virus depletion curve (AUC(VL)) from baseline to day 10 were determined. Laboratory and clinical safety monitoring were performed.


RESULTS
Twenty-four patients were enrolled. The mean VL log(10) change was 0.10 with placebo, -0.69 with zidovudine 200 mg, -0.55 with zidovudine 300 mg, -1.09 with amdoxovir, -2.00 with amdoxovir plus zidovudine (200 mg) and -1.69 with amdoxovir plus zidovudine (300 mg). Amdoxovir plus zidovudine (200 mg) was significantly more potent than amdoxovir monotherapy in AUC(VL) and mean VL decline (P=0.019 and P=0.021, respectively), suggesting synergy. There was markedly decreased VL variability with the combination compared with amdoxovir alone. All adverse events were mild to moderate.


CONCLUSIONS
The combination of amdoxovir plus zidovudine appeared synergistic with reduced VL variability. This combined therapy, including the use of a lower zidovudine dosage, warrants further development for the therapy of HIV infection.
Murphy
Robert L
RL
Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
Kivel
Nancy M
NM
Zala
Carlos
C
Ochoa
Claudia
C
Tharnish
Phillip
P
Mathew
Judy
J
Pascual
Maria Luz
ML
Schinazi
Raymond F
RF
D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D004148:Dioxolanes / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011684:Purine Nucleosides / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load; D055815:Young Adult; D015215:Zidovudine / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
D019380:Anti-HIV Agents; D004148:Dioxolanes; D011684:Purine Nucleosides; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; C098393:amdoxovir
Curr Pharm Des. 2004;10(32):4005-37
15579085
AIDS. 2004 Oct 21;18(15):2094-6
15577635
Antimicrob Agents Chemother. 2008 Dec;52(12):4241-50
18838591
Nucleosides Nucleotides. 1999 Apr-May;18(4-5):891-2
10432704
J Virol. 2006 May;80(10):4971-7
16641288
AIDS. 2007 Jul 11;21(11):1405-14
17589186
AIDS. 2005 Oct 14;19(15):1607-15
16184030
Antimicrob Agents Chemother. 2010 Mar;54(3):1248-55
20038617
Antivir Ther. 2005;10(1):13-28
15751760
J Infect Dis. 2006 Sep 1;194(5):651-60
16897664
N Engl J Med. 2004 Apr 29;350(18):1850-61
15115831
JAMA. 1993 Feb 10;269(6):729-30
8093740
AIDS. 2007 Oct 1;21(15):2025-32
17885292
J Acquir Immune Defic Syndr. 2005 Jan 1;38(1):110-1
15608534
AIDS Patient Care STDS. 2007 Apr;21(4):240-6
17461718
Biochem Pharmacol. 2004 Nov 1;68(9):1879-88
15450953
Antimicrob Agents Chemother. 2000 Jul;44(7):1783-8
10858331
Antivir Ther. 2006;11(5):619-23
16964830
HIV Med. 2004 Nov;5(6):394-9
15544690
Antivir Chem Chemother. 2007;18(6):343-6
18320938
Pharmacotherapy. 2001 Jan;21(1):11-34
11191730
Antimicrob Agents Chemother. 1999 Oct;43(10):2376-82
10508010
J Acquir Immune Defic Syndr. 2002 Jan 1;29(1):11-20
11782585