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DAPD, NRTI - Modestly Reduced Viral Load & No Safety Issues
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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)
Reported by Jules Levin
13th CROI, Denver, Feb 5-8, 2006
....I spoke with researchers and developer of drug who said DAPD development is not hamstrung by formerly suspected toxicity, lens changes. Authors in this study reported... 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.
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
B-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.
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.
40 adults were enrolled (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 (-0.37 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. By Week 2, 10 of 40 patients attained HIV-1 RNA reduction > 0.5 log10 copies/mL.
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). 4 patients with K65R and/or Q151M mutations showed no response to study treatment.
Amdoxovir with or without MMF generally safe and well tolerated: 2 grade 3 toxicities reported by Week 2 (elevated lipase, flatus); 3 additional grade 3 toxicities were observed after Week 4 necessitating treatment discontinuation, the authors said 2 of these 3 events not likely to be related to study treatment.
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.
Authors concluded- 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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