4th International Workshop on HIV Drug Resistance & Treatment Strategies Sitges, Spain, 12–16 June 2000

ACTIVITY OF SJ-3366, A NOVEL NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR OF HIV-1, IN COMBINATION WITH OTHER ANTI-HIV AGENTS AGAINST WILD-TYPE AND SJ-3366-RESISTANT VIRAL ISOLATES

Antivir Ther. 2000 Jun 12-16; 5 (Suppl. 3):9 (Abstract 12

S Palmer¹, JD Russell¹, RW Buckheit Jr¹, J-W Lee², S-H Lee², J-W Oh², H-S Kwon², S-G Chung² and E-H Cho^2
1Southern Research Institute, Frederick, Md., USA; and ²Samjin Pharmaceutical Co., Ltd., Seoul, Korea

INTRODUCTION: The failure of single agent anti- HIV therapy is linked to the rapid replication and subsequent viral diversity of HIV which leads to the emergence of drug-resistant viral strains. Potent and rationally designed chemotherapy combining protease and reverse transcriptase (RT) inhibitors can dramatically slow the progression of HIV infection in patients. In the present study, SJ-3366, a non-nucleoside reverse transcriptase inhibitor which inhibits HIV-1 replication at concentrations below 1 nM and exhibits a therapeutic index of greater than 4,000,000, was evaluated in combination with protease inhibitors as well as other mechanistically diverse inhibitors of HIV-1. These combination assays were conducted against wild-type and SJ-3366-resistant viral isolates.

METHODS: SJ-3366-resistant viruses were selected in vitro by exposing HIV-1_IIIB to dose-escalating treatments of SJ-3366. Three SJ-3366-resistant isolates from the selection assay were utilized for the combination assays: HIV_Y181C (passage 4); HIV_{E6E/K, V106V/I, Y181C, F227L} (passage 13); and HIV_{E6E/K, V106I, Y181C, F227L} (passage 21). SJ-3366 was evaluated in two- and three-drug combination regimens with zidovudine, didanosine, lamivudine, 2′-fluoro-2′,3′-dideoxyarabinosyladenine (F-ddA), nevirapine, efavirenz, indinavir, ritonavir, nelfinavir, ISIS 5320, resobene, NAb 2F5 (anti-gp41) and NAb 2G12 (anti-gp120). These combinations were also tested against wild-type HIV-1_IIIB. Drug interactions were evaluated three dimensionally using the Prichard and Shipman model.

RESULTS: The IC₅₀ values for SJ-3366 were 0.0017, 0.026, 8.5 and >567 μM, respectively, for wild-type, HIV_Y181C, HIV_{E6E/K, V106V/I, Y181C, F227L}, and HIV_{E6E/K, V106I, Y181C, F227} isolates. With wild-type virus, additive to slightly synergistic interactions were seen with most combinations, with some notable exceptions. The two-drug combinations of SJ-3366/didanosine, SJ-3366/F-ddA and SJ-3366/NAb 2G12 demonstrated considerable levels of synergy. In the combination assays using SJ-3366-resistant isolates, higher concentrations of SJ-3366 were required in order to compensate for the level of resistance to SJ-3366. Results for combination assays with SJ-3366-resistant isolates were similar to those for wild-type, however, the three-drug combination of SJ-3366, zidovudine and nevirapine exhibited enhanced synergistic activity against these isolates. None of the combinations analysed showed synergistic cytotoxicity.

CONCLUSIONS: Consistent synergy and/or additivity exhibited in these combinations, and the absence of antagonistic interactions, suggests that SJ-3366 may hold considerable promise in the treatment of HIV, and might be favourably considered for clinical evaluation.

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2000-06-12
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