In vitro NNRTI resistance of recombinant HIV carrying mutations observed in efavirenz treatment failures.
authors
S. JEFFREY, J. CORBETT and L. BACHELER.
publication
6th Conference on Retroviruses and Opportunistic Infections. 31 Jan-4 Feb, 1999, Chicago, IL. Abstract 110.
ABSTRACT
Data from SUSTIVA(TM) (efavirenz) clinical trials suggest a key role of the K103N mutation in HIV RT for viral resistance to this potent non-nucleoside HIV-1 RT inhibitor. Viruses with K103N alone or in combination with other RT mutations were observed in the plasma of the majority of patients exposed to efavirenz who exhibited viral load rebound. Recombinant viruses containing L100I, V108I or P225H alone or combined with K103N were constructed and assayed in an in vitro drug susceptibility assay for resistance to efavirenz, nevirapine, delavirdine, MKC 442, and two new non-nucleoside inhibitors, DMP 961 and DMP 963. Viruses with the single amino acid substitutions V108I and P225H exhibited no resistance to efavirenz, while the K103N virus was 18-fold resistant to efavirenz, and the L100I virus 24-fold. In combination with K103N, resistance to efavirenz increased to 100-120 fold with the addition of either P225H or V108I, and to >2300-fold for the L100I/K103N combination. Similarly, the K103N virus was 37-fold resistant to nevirapine but 180-300-fold resistant in combination with P225H or V108I, and >2300-fold resistant to nevirapine as the combination K103N/L100I. Similar results were obtained for MKC 442. The single mutant P225H was 3-fold more sensitive to delavirdine than WT virus, and the combination K103N/P225H was less resistant to delavirdine than the K103N mutation alone (11 vs. 28-fold). Combinations of K103N with V108I or L100I resulted in increased resistance to delavirdine (45 and 1000-fold). Results for DMP 961 and DMP 963 showed the lowest resistance of the K103N virus, and a corresponding lower resistance of the K103N double mutants. The results suggest that the combinations of mutations observed most frequently in vivo following efavirenz treatment failure confer increased resistance to efavirenz, and a broad cross resistance to the NNRTIs tested.
