Genotypic and phenotypic analysis of HIV-1 from patients receiving combination therapy containing two nucleoside reverse transcriptase inhibitors (NRTIs) and the non-NRTI, emivirine (MKC-442)
Originally Published on September 1, 1999
B McCreedy, K Borroto-Esoda, J Harris, C Klish, L Fang and D Miralles
ABSTRACT:
Emivirine is a potent non-nucleoside reverse transcriptase inhibitor (NNRTI) that was well tolerated with twice daily dosing in Phase I/II trials. Therapy-naïve patients were enrolled in two randomized, double-blind, placebo-controlled studies to examine the addition of emivirine in patients initiating therapy with stavudine/lamivudine (MKC-301) or stavudine/didanosine (MKC-302). HIV RNA was measured in each study to assess the magnitude and durability of antiviral activity of the drug combinations and the results were provided in real time.
To determine whether antiviral drug resistance was associated with therapy failure, all patients who experienced a protocol-defined virological failure had DNA sequence analysis performed for the polymerase gene of HIV isolated from plasma specimens from the baseline and failure visits. Of 138 patients in both studies who were randomized to emivirine, mutations associated with resistance to NNRTIs were observed for 23/138. The NNRTI mutations observed were K103N (13/23), G190A (2/23), Y181C (2/23), A98S/K101E (1/23), K101E/V106M/V (1/23), V108I (1/23) and E138K (1/23). Single mutations at E138Q (1/23) and A98S (1/23) were observed which have not been shown previously to confer resistance to NNRTIs.
To study the effect of these mutations on the antiviral activity of emivirine, recombinant viruses were generated that contained the RT gene from the patients' plasma HIV. The recombinant viruses containing the mutant RT genes were assayed in vitro for susceptibility to emivirine, delavirdine, efavirenz and nevirapine as well as to a panel of NRTIs. Viruses containing a K103N mutation were resistant to emivirine and were also resistant to efavirenz, delavirdine and nevirapine. Viruses containing mutations at K101E, V108I, Y181C or G190A showed varying levels of resistance to emivirine but remained sensitive to one or more of the other NNRTIs. The results of these studies indicate that patients receiving combination therapy who experience a loss of virus suppression associated with the development of resistance to emivirine, but do not harbor K103N mutant HIV in plasma (10/23, 43.5%), appear to remain sensitive to at least one other approved NNRTI.
