Grahic Jump LocationFor each amino acid residue, the letter above indicates the amino
acid associated with wild-type virus; the italicized letters below, substitutions
that confer viral resistance. Primary mutations (black bars) generally cause
decreased inhibitor binding and are the first mutations selected. Secondary
mutations (white bars) also contribute to drug resistance and should be considered
as evidence of resistance, although they may have less direct effect on inhibitor
binding in vitro than primary mutations. The mutation selected in vitro (black-and-white
bar) is rarely seen in patients having treatment failure. For indinavir, the
mutations listed as primary may not be the first mutations selected, but they
are selected in most patient isolates in combination with other mutations.
For zalcitabine, all mutations are listed as primary because of inadequate
clinical data to determine the most frequent initial mutation. Amino acid
abbreviations are: A, alanine; C, cysteine; D, aspartate; E, glutamate; F,
phenylalanine; G, glycine; H, histidine; I, isoleucine; K, lysine; L, leucine;
M, methionine; N, asparagine; P, proline; Q, glutamine; R, arginine; S, serine;
T, threonine; V, valine; W, tryptophan; Y, tyrosine. Multinucleoside resistance
mutational patterns A and B each cause resistance to zidovudine, stavudine,
lamivudine, didanosine, zalcitabine, and abacavir. Current listings are also
available at
http://www.iasusa.org/.
*Mutations selected
by protease inhibitors in
gag cleavage sites are
not listed because their contribution to resistance is not fully defined.
†
A preliminary report identifies mutations E44D and V118I as conferring moderately
reduced (about 10-fold) susceptibility to lamivudine with uncertain clinical
significance.
22 This contrasts with the greater
than 100-fold reduced susceptibility to lamivudine conferred by M184V or M184I,
which is associated with virologic rebound.
14- 16‡
The mutations listed for zidovudine above contribute to reduced susceptibility
to abacavir in vitro and in vivo and are listed as secondary, even though
they may be present before abacavir is introduced.
23- 24
They have also been reported to be uncommonly selected by stavudine plus didanosine
even in the absence of prior zidovudine exposure.
25- 27
Phenotypic resistance of these mutations to stavudine or didanosine in vitro
was not identified. The clinical significance of these mutations and of V75T
on in vivo response to stavudine is not known.
§ Several insertions
of 2 amino acids have been reported following T69S (or rarely T69A), including
Ser-Ser; Ser-Gly; Ser-Ala; Glu-Ala; and Thr-Ser.
28- 29∥
For nevirapine or delavirdine, each mutation can occur as an initial or subsequent
mutation and affect inhibitor binding.
30- 32