The use of beta-D-2,6-diaminopurine dioxolane with or without mycophenolate mofetil in drug-resistant HIV infection.

TitleThe use of beta-D-2,6-diaminopurine dioxolane with or without mycophenolate mofetil in drug-resistant HIV infection.
Publication TypeJournal Article
Year of Publication2007
AuthorsMargolis DM, A Mukherjee L, Fletcher CV, Hogg E, Ogata-Arakaki D, Petersen T, Rusin D, Martinez A, Mellors JW
JournalAIDS
Volume21
Issue15
Pagination2025-32
Date Published2007 Oct 1
ISSN0269-9370
KeywordsAdult, Aged, Dioxolanes, Double-Blind Method, Drug Resistance, Viral, Drug Therapy, Combination, Female, HIV Infections, HIV-1, Humans, Immunosuppressive Agents, Male, Middle Aged, Mycophenolic Acid, Purine Nucleosides, RNA, Viral, Treatment Outcome, Viral Load
Abstract

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.

DOI10.1097/QAD.0b013e3282364381
Alternate JournalAIDS
PubMed ID17885292
Grant List5P30 AI 50409 / AI / NIAID NIH HHS / United States
AI 027666 / AI / NIAID NIH HHS / United States
AI 032783 / AI / NIAID NIH HHS / United States
AI 045008 / AI / NIAID NIH HHS / United States
AI 046376 / AI / NIAID NIH HHS / United States
AI 25879 / AI / NIAID NIH HHS / United States
AI 25903 / AI / NIAID NIH HHS / United States
AI 27661 / AI / NIAID NIH HHS / United States
AI 27664 / AI / NIAID NIH HHS / United States
AI 32770 / AI / NIAID NIH HHS / United States
AI 34853 / AI / NIAID NIH HHS / United States
AI 38855 / AI / NIAID NIH HHS / United States
AI 38858 / AI / NIAID NIH HHS / United States
RR 00051 / RR / NCRR NIH HHS / United States