The use of beta-D-2,6-diaminopurine dioxolane with or without mycophenolate mofetil in drug-resistant HIV infection.
OBJECTIVE
We evaluated the safety, tolerability and antiretroviral activity of beta-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/microl, 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 < or = 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.
Margolis
David M
DM
University of North Carolina at Chapel Hill, 3302 Michael Hooker Research Center, Chapel Hill, NC 27599, USA. dmargo@med.unc.edu
Mukherjee
A Lisa
AL
Fletcher
Courtney V
CV
Hogg
Evelyn
E
Ogata-Arakaki
Debra
D
Petersen
Tianna
T
Rusin
David
D
Martinez
Ana
A
Mellors
John W
JW
D000328:Adult; D000368:Aged; D004148:Dioxolanes / Q000627:therapeutic use*; D004311:Double-Blind Method; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011684:Purine Nucleosides / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D016896:Treatment Outcome; D019562:Viral Load
D004148:Dioxolanes; D007166:Immunosuppressive Agents; D011684:Purine Nucleosides; D012367:RNA, Viral; C098393:amdoxovir; D009173:Mycophenolic Acid