Isolates carrying the L100I or K103N mutations have a 20- to 30-fold increase in IC90 to efavirenz compared to wild-type isolates. The combination of K103N with either L100I, V108I or P225H leads to an increase in IC90 of 100-fold or greater.
Cross-resistance:
In theory, isolates carrying only the L100I mutation may remain susceptible to delavirdine and nevirapine. However, this pattern is virtually never observed. Therefore, for all practical purposes, isolates resistant to efavirenz should be considered resistant to delavirdine and nevirapine.
Emergence of resistance in vivo:
This occurs relatively rapidly in subjects receiving efavirenz therapy in the absence of maximal virologic suppression. In the vast majority of cases, the K103N mutation appears first. Continued exposure to efavirenz leads to the accumulation of additional mutations associated with higher levels of efavirenz resistance. In a small number of patients (<10%), an alternative path to efavirenz resistance is followed, with the Y188L and/or G190S mutations appearing.
Clinical correlates of resistance:
If therapy is continued in the presence of the K103N mutation, a rebound in plasma viral load is observed over the next 60-90 days. The addition of supplementary mutations (L100I, V108I, P225H) hastens the onset of virologic failure, which is then followed by a progressive decrease in CD4 cell counts.
Other comments:
In contradistinction with other NNRTIs, the emergence of high-level resistance to efavirenz may require the accumulation of multiple mutations within the same viral genome. In this way, the barrier to resistance may be somewhat higher. The clinical benefit (if any) of this concept as it relates to efavirenz has yet to be determined.
Desire N, Amiel C, Schneider V, Delphin N, Dam E, Clavel F, Nicolas JC, Rozenbaum W. An HIV-1 isolate with the mutation G190E and an insertion between codons 100-105 of reverse transcriptase: phenotypic resistance implications.Antiviral Ther 2002; 7:S35.
Efavirenz (EFV), Sustiva, DMP-266
