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A Phase I/II Randomized, Double-blind, Placebo-controlled Pilot Study of b-D-2,6-Diaminopurine Dioxolane Vs DAPD + Mycophenolate Mofetil in Treatment-experienced Subjects (ACTG 5165)
David Margolis*1, L Mukherjee2, E Hogg3, C Fletcher4, D Ogata-Arakaki5, T Petersen6, D Rusin7, A Martinez8, E Adams8, J Mellors9, and Adult AIDS Clinical Trials Group A5165 team
1Univ of North Carolina at Chapel Hill, US; 2Harvard Sch of Publ Hlth, Boston, MA, US; 3Social & Sci Systems, Silver Spring, MD, US; 4Univ of Colorado Hlth Sci Ctr, Denver, US; 5Univ of Hawaii, Manoa, US; 6Univ of Texas Southwestern Med Ctr, Dallas, US; 7Frontier Sci & Tech Res Fndn, Amherst, NY, US; 8NIAID, NIH, DHHS, Bethesda, MD, US; and 9Univ of Pittsburgh, PA, US
Background: β-D-2,6-Diaminopurine
dioxolane (DAPD)
is a guanosine nucleoside analog reverse
transcriptase inhibitor (NRTI) with in
vitro activity against wild type and most NRTI-resistant HIV-1. Mycophenolate mofetil (MMF), an
inhibitor of de novo guanosine nucleotide synthesis, increases DAPD potency
against NRTI-resistant HIV-1 in vitro.
ACTG 5165 evaluated the safety, tolerability, and antiviral activity of DAPD with
or without MMF in heavily pre-treated subjects.
Methods: At entry, subjects added DAPD 500 mg twice daily
+ MMF placebo twice daily (n = 20),
or DAPD 500 mg twice daily + MMF 500 mg twice daily (n = 20) to their failing regimens, which excluded abacavir. Primary endpoints at week 2 were analyzed by
intent-to-treat, using rank-based tests. The geometric mean of the pre-entry +
entry HIV-1 RNA was compared with week 2 viral load. Subjects responding to
DAPD with or without MMF (viral load decline from baseline ≥0.5 log10)
at week 2 optimized ART and continued study therapy for as long as 96 weeks.
Results: We enrolled 40 adults (male, 90%; white, 55%; 40 to 49 years of age, 70%) with
viral load ≥2000 copies/mL (median 4.47 log10
copies/mL) and CD4+ cell count ≥50
cells/mm3 (median 184 cells/mm3). At entry, subjects had
a median of 6 (range 1 to 8) NRTI mutations (IAS-USA). Other characteristics between
the arms were balanced. A significant decline in viral load (median –0.26 log10,
p <0.0001) was seen in the pooled
treatment arms at week 2. There was no significant difference between the DAPD
alone (–0.35 log10) and DAPD + MMF (–0.24 log10) arms. Of
40 subjects, 10 had a virologic response at week 2; of
10 responses, 4 persisted after week 2. As expected, the 4 subjects with K65R
or Q151M complex did not respond. Among the remaining subjects, virologic response was associated with the baseline
genotype having ≤5 NRTI mutations (p
= 0.12) and <4 thymidine analog mutations (TAM)
without E44D or V118I (p =0.08).
There were 2 grade 3 events by week 2, not clearly related to study treatment. After
week 2, 31 subjects continued on study, and 5 beyond week 24. Potential
drug-related toxicities such as CD4+ cell decline <50% of
baseline, significant lens changes, or ≥grade 2 renal or glucose
toxicities were not observed.
Conclusions: DAPD and MMF were safe and well tolerated.
DAPD monotherapy had modest antiretroviral activity (–0.35
log10) in heavily pre-treated subjects with extensive NRTI
resistance. In contrast to synergy observed in
vitro, DAPD activity over 2 weeks was not increased by MMF (500 mg twice
daily) in this study. Assays of DAPD and MMF exposure are underway to
investigate this discrepancy.
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