AEGiS-13IAC: Potent Antiviral Activity of Second Generation NNRTIs DPC 961 and DPC 083 against Group M and Group O strains of HIV-1.

13th International AIDS Conference

Durban, South Africa - July 9-July 14, 2000

Potent Antiviral Activity of Second Generation NNRTIs DPC 961 and DPC 083 against Group M and Group O strains of HIV-1.

Int Conf AIDS 2000 Jul 9-14; 13:(abstract no. WeOrA536)

Bacheler L, Jeffrey S, Verbiest W, Hertogs K, Larder B
L. Bacheler, DuPont Pharmaceuticals Co, E336/36B Experimental Station, Wilmington, DE 19880-0336, United States, Tel.: +1-302-695 42 78, Fax: +1-302-695 94 66, E-mail: lee.bacheler@dupontpharma.com

INTRODUCTION: First generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1 have demonstrated clinical utility in HAART regimens for NNRTI naive patients. However, clinically significant resistance to these agents can arise from a single point mutation in the reverse transcriptase (RT) gene of HIV-1. Increasing global circulation of a wide variety of HIV-1 strains distinct from the Clade B subtypes currently predominant in Western Europe and North America suggests that discovery and development of agents effective against the widest possible diversity of virus strains is critical. Two new second generation NNRTIs, DPC 961 and DPC 083, have been identified with improved potency against NNRTI resistant strains.

METHODS: A recombinant virus assay was used to assess the in vitro drug susceptibility of clinical isolates of HIV-1 to DPC 961 and DPC 083. HIV-1 isolates representative of subtypes A-H of Group M, Group O isolates, and isolates from patients failing efavirenz combination therapy were tested.

RESULTS: Most Group M isolates from therapy naive patients were susceptible to DPC 961 and DPC 083 as well as to the first generation NNRTIs nevirapine (NVP), delavirdine (DLV) and efavirenz (EFV) with mean IC50s of 0.36 nM (DPC 961) to 0.40 nM (DPC 083). Five isolates (subtypes B, C, H, and A/E), each with low level resistance to one or more of the first generation NNRTIs, were susceptible to DPC 083 and/or DPC 961. A group O isolate with resistance to NVP(>65X), DLV(95X), and EFV(36X) showed less resistance to DPC 961 (8X) and DPC 083 (24X). Isolates from patients failing efavirenz showed reduced resistance to DPC 961 and DPC 083 compared to EFV. The mean IC50 values were 7 nM ( DPC 961), 28nM (DPC 083) and 43nM (EFV) for 7 isolates with a K103N mutation and 25 nM ( DPC 961), 100 nM ( DPC 083), and >190 nM(EFV) for 16 isolates with multiple NNRTI resistance mutations including K103N.

CONCLUSIONS: DPC 961 and DPC 083 have demonstrated overall improvements in potency against isolates from Group M and O strains of HIV-1 as well as clinical isolates from patients failing efavirenz combination therapy. It is anticipated that human plasma trough levels of these inhibitors will be sufficient to inhibit a broad range of HIV-1 strains in therapy naive patient populations as well as most clinically relevant NNRTI resistant strains in NNRTI experienced patient populations.

Keywords: AEGIS, HIV-1, Reverse Transcriptase Inhibitors, Nevirapine, HIV-1 Reverse Transcriptase, Oxazines, Delavirdine, Quinazolines, Antiretroviral Therapy, Highly Active, RNA-Directed DNA Polymerase, Mutation, Europe, North America, efavirenz, DPC 083, DPC 961, Human, genetics
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