Objective: We evaluated the safety, tolerability and antiretroviral activity of β-D-2,6-diaminopurine dioxolane (DAPD; amdoxovir) with or without mycophenolate mofetil (MMF) in HIV-1 infection following extensive antiretroviral therapy (ART).
Methods: Oral DAPD 500 mg twice daily with placebo or MMF 500 mg twice daily was added to failing ART. HIV-1 RNA viral load (VL) decline to week 2 was analyzed by intent-to-treat, using rank-based tests. Patients with VL decline > 0.5 log10 copies/ml at week 2 (virologic response, VR) optimized ART and continued therapy for up to 96 weeks.
Results: Forty adults with median VL 4.5 log10 copies/ml, median 184 CD4+ cells/μl, and a median of 6 nucleoside reverse transcriptase inhibitor (NRTI) mutations (range, 1–8) were randomized. Median VL reduction at week 2 was −0.26 log10 copies/ml (P < 0.0001). Response to DAPD/placebo (median −0.37 log10 copies/ml) was unexpectedly greater than to DAPD/MMF (median −0.23 log10 copies/ml), although this difference was not statistically significant (P = 0.59). MMF appeared to lower concentrations of DAPD and its metabolite dioxolane guanosine. Of 10 patients with VR (DAPD 7, DAPD/MMF 3), four persisted beyond week 24. VR was more frequent with ≤ 5 baseline NRTI mutations (P = 0.12) or < 4 thymidine-associated mutations (TAMs) without E44D or V118I (P = 0.08). Twenty-three patients received extended DAPD +/− MMF; five beyond week 24. Few adverse events were related to study medications.
Conclusions: The addition of DAPD +/− MMF to failing therapy appears safe and well tolerated. DAPD had significant activity at week 2 (mean −0.35 log10) in heavily pretreated patients that was not augmented by MMF.
From the aUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
bHarvard School of Public Health, Boston, Massachusetts, USA
cUniversity of Colorado Health Sciences Center, Denver, Colorado, USA
dSocial & Scientific Systems, Silver Spring, Maryland, USA
eUniversity of Hawaii at Manoa, Hawaii, USA
fUniversity of Texas Southwestern, Dallas, Texas, USA
gFrontier Science & Technology Research Foundation, Amherst, New York, USA
hNIAID, National Institutes of Health, Bethesda, Maryland, USA
iUniversity of Pittsburgh, Pennsylvania, USA.
Received 2 December, 2006
Revised 12 February, 2007
Accepted 30 April, 2007
Correspondence to David M. Margolis, MD, University of North Carolina at Chapel Hill, 3302 Michael Hooker Research Ctr., CB#7435, Chapel Hill, NC 27599-7435. Tel: +919 966 6388; fax: +919 966 0584; e-mail: email@example.com