Drug Resistance Mutations in HIV-1

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					                                          Special Contribution - Drug Resistance Mutations            Volume 10 Issue 2 May/June 2002




Drug Resistance Mutations in HIV-1
Richard T. D’Aquila, MD, Jonathan M. Schapiro, MD, Françoise Brun-Vézinet, MD, PhD, Bonaventura
Clotet, MD, PhD, Brian Conway, MD, Lisa M. Demeter, MD, Robert M. Grant, MD, MPH, Victoria A.
Johnson, MD, Daniel R. Kuritzkes, MD, Clive Loveday, MD, PhD, Robert W. Shafer, MD, and Douglas D.
Richman, MD

New information continues to accumu-             mutation confers resistance to the spe-           its contribution to phenotypic resistance
late on drug resistance mutations in             cific drug.                                       to abacavir.
HIV-1 and their relevance to clinical
practice. The Drug Resistance Mutations          Content Changes                                    Figure Pocket Card Available
Group of the International AIDS
                                                                                                    The IAS–USA Drug Resistance Mutations
Society–USA (IAS–USA), originally a              In this revision, “primary” or “secondary”         Figures are now available on a pocket-sized
subgroup of the IAS–USA Resistance               mutations in the protease gene have                folding card. To order copies, please call the
Testing Guidelines Panel,1 monitors the          been redefined as “major” or “minor”               IAS–USA at (415) 561-6720 or e-mail your
influx of information and maintains a                                                               request to resistance@iasusa.org.
                                                 mutations to avoid confusion regarding
current list of mutations that impact            the order in which the mutations may
drug susceptibility. This list is published      occur. In general, major mutations are
as the IAS–USA Drug Resistance                   either (1) selected first by the drug; or         Future Updates
Mutations Figures and is updated regu-           (2) are shown at the biochemical or viro-
larly. The most recent update and adap-                                                            The IAS-USA Drug Resistance Mutations
                                                 logic level to lead to an alteration in
tation was published in this journal and                                                           Group will consider the next update after
                                                 drug binding or an inhibition of viral
posted on the IAS–USA Web site                                                                     the 6th International Workshop on HIV
                                                 activity or replication. By themselves,
(www.iasusa.org) in December 2001.2                                                                Drug Resistance and Treatment
                                                 major mutations have an effect on phe-
The new graphic presented here                                                                     Strategies, to be held in June 2002 in
                                                 notype. In general, these mutations tend
includes relevant data presented at the                                                            Seville, Spain. In the meantime, we wel-
                                                 to be the major contact residues for drug
9th Conference on Retroviruses and Op-                                                             come evidence-based comments to this
                                                 binding. On the protease inhibitor fig-
portunistic Infections, held in Seattle,                                                           paper. Please send your comments,
                                                 ure, the codon numbers for major muta-
Wash, in February 2002.3                                                                           along with the relevant supporting refer-
                                                 tions are marked in boldface type (see
                                                                                                   ence citations, to resistance@iasusa.
                                                 key).
                                                                                                   org; submissions will be considered for
New Graphic Display                                Minor mutations, in general, appear
                                                                                                   the next update.
                                                 later than major mutations, and by
These new figures feature a simpler              themselves have not been shown to
graphic display of the information for           have a significant effect on phenotype.           References
easier reference. The nucleotide reverse         In some cases, their effect may be to             1. Hirsch MS, Brun-Vézinet F, D’Aquila RT, et al.
transcriptase inhibitor (ntRTI) category,        improve replicative fitness of virus carry-       Antiretroviral drug resistance testing in adult
including only tenofovir disoproxil              ing major mutations. On the protease              HIV-1 infection: recommendations of an
                                                                                                   International AIDS Society–USA Panel. JAMA.
fumarate (tenofovir DF), has been com-           gene figure, the codon numbers for                2000;283:2417-2426.
bined with the nucleoside reverse tran-          minor mutations are marked in lightface
                                                                                                   2. International AIDS Society–USA Resistance
scriptase inhibitor (nRTI) category. For         type (see key).
                                                                                                   Mutations Group. Update on drug resistance
all mutations, the codon number, rather            Other changes to the figures include            mutations in HIV-1. Topics in HIV Medicine.
than a mark, appears on the gene.                noting the effect of the E44D mutation            2001;9(6):21-23.
Finally, the nRTI-associated mutations           on response to zidovudine, clarifying the
                                                                                                   3. 9th Conference on Retroviruses and Oppor-
(NAMs) are indicated as pink lines in the        role of the V108I and P225H mutations             tunistic Infections. Available at: http:
background. Where a codon number                 to efavirenz resistance, and adding an            //www.retroconference.org. Accessed May 23,
marks the NAM, data indicate that the            explanation of the M184V mutation and             2002.




Author Affiliations: Dr D’Aquila (Group Chair), Vanderbilt University     of Virology and Immunology, San Francisco, Calif; Dr Johnson, The
Medical Center, Nashville, Tenn; Dr Schapiro (Group Vice-chair),          University of Alabama at Birmingham; Dr Kuritzkes, Brigham and
Sheba Medical Center, Tel Aviv, Israel, and Stanford University School    Women’s Hospital, Harvard Medical School, Boston, Mass; Dr
of Medicine, Palo Alto, Calif; Dr Brun-Vézinet, Hôpital Bichat-Claude     Loveday, International Clinical Virology Centre, Buckinghamshire,
Bernard, Paris, France; Dr Clotet, Fundacio irsiCAIXA and HIV Unit,       England; Dr Shafer (Consultant), Stanford University Medical School,
Hospital Universitari Germans Trias i Pujol, Barcelona, Spain; Dr         Palo Alto, Calif; Dr Richman, University of California San Diego and
Conway, University of British Columbia, Vancouver; Dr Demeter,            Veterans Affairs San Diego Healthcare System, La Jolla, Calif.
University of Rochester, Rochester, NY; Dr Grant, Gladstone Institute


                                                                     11
International AIDS Society–USA    Topics in HIV Medicine



    MUTATIONS IN THE REVERSE TRANSCRIPTASE GENE ASSOCIATED WITH RESISTANCE TO
    REVERSE TRANSCRIPTASE INHIBITORS

    Nucleoside and Nucleotide Reverse Transcriptase Inhibitors
      Multi-nRTI
      Resistance:
    151 Complex
      Multi-nRTI
      Resistance:
     69 Insertion
                1
       Complex

      Multi-nRTI
                2
      Resistance
         (NAMs)


                 3–5
    Zidovudine



                   6
     Didanosine



      Zalcitabine


                 3,7
     Stavudine




                   8
        Abacavir



                   9
     Lamivudine



                3,10
  Tenofovir DF



    Nonnucleoside Reverse Transcriptase Inhibitors

    Multi-NNRTI
              11
    Resistance

     Multi-NNRTI
       Resistance
   (accumulation
                12
  of mutations)



      Nevirapine



                 13
    Delavirdine


              13,14
    Efavirenz




                                                             12
                                              Special Contribution - Drug Resistance Mutations                        Volume 10 Issue 2 May/June 2002



        MUTATIONS IN THE PROTEASE GENE ASSOCIATED WITH RESISTANCE TO PROTEASE INHIBITORS
        Protease Inhibitors15
      Multi-Protease
            Inhibitor
           Resistance
       (accumulation
                    16
      of mutations)


                     17
           Indinavir




            Ritonavir




          Saquinavir




           Nelfinavir




         Amprenavir




           Lopinavir/
                  18,19
         Ritonavir



                                                                    MUTATIONS
                                                                             Insertion       See Footnote 18
                                        Amino Acid, Wild-Type                                           See Footnote 19

                                         Amino Acid Position
                          Major (boldface type; protease only)
                                     Amino Acid, Substitution
                                                                                                    See Footnote 7
                                                                 Vertical pink lines   Minor (lightface type; protease only)
                                                                  indicate NAMs




For each amino acid residue, the letter above the bar indicates the amino acid associated                      Amino acid abbreviations are: A, alanine;
with wild-type virus and the letter(s) below indicate the substitution(s) that confer viral resis-             C, cysteine; D, aspartate; E, glutamate; F,
tance. The number shows the position of the mutation in the protein. Mutations selected                        phenylalanine; G, glycine; H, histidine; I,
by protease inhibitors in Gag cleavage sites are not listed because their contribution to resis-               isoleucine; K, lysine; L, leucine; M, methion-
tance is not yet fully defined. NAMs indicates nRTI-associated mutations; nRTI indicates                       ine; N, asparagine; P, proline; Q, glutamine; R,
nucleoside reverse transcriptase inhibitor; NNRTI indicates nonnucleoside reverse transcrip-                   arginine; S, serine; T, threonine; V, valine; W,
tase inhibitor. The figures were last published in this journal in December 2001.                              tryptophan; Y, tyrosine.




                                                                                13
International AIDS Society–USA         Topics in HIV Medicine



Footnotes                                      abacavir. However, when present alone,        present. However, confirmatory data
                                               the M184V mutation does not appear to         and/or analyses in clinical HIV infection
1
 The 69 insertion complex, consisting of       be associated with a reduced virologic        are needed to confirm clinical relevance.
a mutation at codon 69 (typically T69S)        response to abacavir.
and followed by an insertion of 2 or                                                         14
                                                                                               V108I and P225H each contribute to
more amino acids (S-S, S-A, S-G, or oth-       9
                                                One article reports that the E44D or         efavirenz resistance when present in
ers), is associated with resistance to sev-    V118I mutation confers low-level resis-       combination with other NNRTI muta-
eral nRTIs. The 69 insertion is often          tance to lamivudine when accompanied          tions. Although V108I or P225H alone
accompanied by mutations at other              by several of the NAMs (M41L, D67N,           does not confer measurable resistance
sites. Some other amino acid changes           L210W, T215Y/F, K219Q/E) in the               in laboratory strains of HIV-1, their pres-
from the wild-type T in codon 69 without       absence of a concurrent M184V muta-           ence in a clinical isolate may indicate
the insertion may also be associated           tion (Hertogs et al, Antimicrob Agents        prior selection for efavirenz-resistant
with broad nRTI resistance.                    Chemother,    2000).    One    abstract       variants.
                                               (D’Arminio-Monforte et al, 8th CROI,
2
 Multi-nRTI-associated   mutations             2001), reported no association over the        The Drug Resistance Mutations Group
                                                                                             15

(NAMs): mutations associated with              short term between E44D or V118I and          has reclassified resistance mutations in
cross-resistance to nRTIs (except              virologic response to a lamivudine-con-       the protease gene as either “major” or
lamivudine).                                   taining combination regimen.                  “minor” rather than “primary” or “sec-
                                                                                             ondary” (if known).
3
 The reverse transcriptase mutation             In vitro data suggest that 4 or more
                                               10
                                                                                                Major: In general, major mutations
M184V may enhance susceptibility. This         NAMs (M41L, D67N, K70R, L210W,                   are either (1) selected first by the
effect may be overcome by an accumula-         T215Y/F, K219Q/E) will lead to a signifi-        drug; or (2) are shown at the bio-
tion of NAMs. The clinical significance of     cant degree of resistance; the actual            chemical or virologic level to lead to
this effect is not known.                      clinical cut-off for tenofovir DF IC50 or a      an alteration in drug binding or an
                                               detailed relationship between specific           inhibition of viral activity or viral
4
 One study reported that the E44D or           multiple NAMs and tenofovir DF IC50 has          replication. By themselves, major
V118I mutation confers lamivudine              not yet been published. Clinical trial           mutations have an effect on pheno-
resistance in a zidovudine-resistant           results indicate reduced plasma HIV-1            type. In general, these mutations
background (Hertogs et al, Antimicrob          RNA responses to tenofovir DF in                 tend to be the major contact residues
Agents Chemother, 2000). Analysis from         groups of patients in whose plasma               for drug binding.
AIDS Clinical Trials Group 241 associat-       virus 3 or more NAMs, including either
ed the E44D mutation with a significant-       M41L or L210W, were identified (Miller             Minor: In general, minor mutations
ly worse response to treatment with            et al, 9th CROI 2002). The group of                appear later than major mutations,
zidovudine and didanosine, with or             patients with plasma virus in which any            and by themselves have not been
without nevirapine (Precious et al, AIDS,      accumulation of D67N, K70R, T215Y/F, or            shown to have a significant effect on
2000).                                         K219Q/E were identified (in the absence            phenotype. In some cases, their
                                               of detection of M41L or L210W) did not             effect may be to improve replicative
5
 The D/C/S substitutions in reverse tran-      have a diminished average HIV-1 RNA                fitness of virus carrying major muta-
scriptase codon 215 do not confer              response to tenofovir DF in that data              tions.
zidovudine resistance and suggest that         set.
virus evolved from the zidovudine-resis-                                                      Accumulation of these mutations (4 or
                                                                                             16

tant mutant T215Y to a variant that is         11
                                                 The K103N or Y188L mutation by itself       5 or more) is likely to cause multi-pro-
more fit in the absence of drug. In vitro      can substantially reduce the clinical util-   tease inhibitor resistance.
studies indicate that T215Y may emerge         ity of all currently approved NNRTIs.
quickly from T215D/C/S in the presence                                                       17
                                                                                              For indinavir, the mutations listed as
of drug; in vivo relevance is possible but     12
                                                Accumulation of these mutations (2 or        major may not be the first mutations
not yet proven.                                more) substantially reduces the clinical      selected, but they are present in most
                                               utility of all of the currently approved      patient isolates in combination with
6
 One of the following (K65R, L74V) by          NNRTIs.                                       other mutations.
itself or a combination of a few of the
                                               13
following (NAMs, E44D, T69D/N, V118I)            There are some in vitro data suggesting     18
                                                                                               Major and minor mutations have not
can lead to didanosine resistance.             that the Y318F mutation, alone or in the      been designated for lopinavir/ritonavir-
                                               presence of K103N and Y181C, de-              associated resistance since there are
7
 V75T/M/S/A are seldom observed in             creased susceptibility to delavirdine in      currently no clear data defining degrees
patients in whom stavudine has failed.         primary HIV infection. This mutation          of influence with this drug combination.
                                               was observed only rarely in clinical iso-     The accumulation of 6 or more of these
8
  When present with NAMs, the M184V            lates. An effect of the Y318F mutation on     mutations is associated with a dimin-
mutation is selected by abacavir and           efavirenz susceptibility in vitro was         ished response to lopinavir/ritonavir.
contributes to phenotypic resistance to        detected if the K103N mutation was also       The product information states that 7 or


                                                                   14
                                              Special Contribution - Drug Resistance Mutations           Volume 10 Issue 2 May/June 2002



8 mutations confer resistance to the                bioMérieux, GlaxoSmithKline, PE Biosystems,       Dr Kuritzkes has served as a consultant to
drug. However, more recent data suggest             Visible Genetics, and Bristol-Myers Squibb; and   Abbott, Bristol-Myers Squibb, Chiron, Gilead,
                                                    has served as a consultant to Visible Genetics    GlaxoSmithKline, Roche, Trimeris, Triangle,
as few as 4 mutations can be associated
                                                    and GlaxoSmithKline.                              Tibotec-Virco, Visible Genetics, and ViroLogic;
with high-level resistance (Prado et al,                                                              has received honoraria from Abbott, Bristol-
AIDS, 2002). Further clinical experience            Dr Clotet has received grant support from         Myers Squibb, Gilead, GlaxoSmithKline,
and research are needed to better define            Roche, Gilead, Bristol-Myers Squibb, and          ViroLogic, and Roche; and has received grant
the mutations that affect the effective-            Visible Genetics.                                 support from Agouron, Bristol-Myers Squibb,
                                                                                                      GlaxoSmithKline, Roche, Tanox, Trimeris,
ness of lopinavir/ritonavir.
                                                    Dr Conway has received research support from      Triangle, and Visible Genetics.
19
 Protease mutation L63P is common in                Boehringer Ingelheim and has received research
                                                    funding from Abbott, Agouron, Bristol-Myers       Dr Loveday has served as a consultant to
viruses that have never been exposed to
                                                    Squibb, Triangle, and Schering.                   GlaxoSmithKline and Visible Genetics; has
protease inhibitors (Kozal et al, Nat Med,                                                            served as a scientific advisor to GlaxoSmith-
1996) and may be more prevalent in                  Dr D’Aquila has served as a speaker or on a       Kline, Visible Genetics, Roche, Boehringer
viruses from patients in whom a pro-                speakers bureau for Agouron, Bristol-Myers        Ingelheim, Bristol-Myers Squibb, and Abbott;
tease inhibitor-containing regimen has              Squibb, Visible Genetics, Gilead, and ViroLogic   and has received grant support from
failed. However, by itself, protease                and as a consultant to GlaxoSmithKline and        GlaxoSmithKline, Visible Genetics, Roche, and
                                                    Bristol-Myers Squibb.                             Abbott.
mutation L63P does not cause any
appreciable increase in the IC50 for any            Dr Demeter has served on the speakers bureau      Dr Richman has served as a consultant to Pfizer,
protease inhibitor. L63P is listed for              and scientific advisory committee for             Merck, Roche, GlaxoSmithKline, Bristol-Myers
lopinavir/ritonavir (and not any other              GlaxoSmithKline and has received research         Squibb, ViroLogic, Gilead, Abbott, Triangle,
protease inhibitor) because the pre-                support from Applied Biosystems and Bristol-      Chiron, Tibotec-Virco, Novirio, and Achillion.
                                                    Myers Squibb/DuPont Merck.
scribing information approved by the US                                                               Dr Schapiro has served as a scientific advisor to
Food and Drug Administration lists it as            Dr Grant has served as a consultant to Visible    Roche and Visible Genetics; has served on the
one of the numerous mutations that                  Genetics; has received honoraria from             speakers bureau for Abbott, Roche, and Bristol-
together predict a lack of viral load               ViroLogic, Agouron, and GlaxoSmithKline; and      Myers Squibb; and has received other financial
response to lopinavir/ritonavir-contain-            has received research support from Virco,         support from GlaxoSmithKline and Virology
                                                    Visible Genetics, and ViroLogic.                  Education.
ing regimens.
                                                    Dr Johnson has served as a consultant to          Dr Shafer has served on the speakers bureau for
                                                    GlaxoSmithKline and Bristol-Myers Squibb; has     Bristol-Myers Squibb, GlaxoSmithKline, and
Financial Disclosure: The authors disclose the      served as a speaker or on a speakers bureau for   Merck; and has received grant support from
following affiliations with commercial supporters   Roche, Bristol-Myers Squibb, GlaxoSmithKline,     Abbott, Agouron, Applied Biosystems, Boeh-
                                                    Chiron, Boehringer Ingelheim/Roxane, Abbott,      ringer Ingelheim, Bristol-Myers Squibb, Gilead,
that may have interests related to the content of
                                                    Merck, Vertex, and ViroLogic; and has received    GlaxoSmithKline, Merck, Roche, and Visible
this article.                                       grant support from GlaxoSmithKline, Boeh-         Genetics.
                                                    ringer Ingelheim, Bristol-Myers Squibb, and
Dr Brun-Vézinet has received grant support from     Visible Genetics.




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