Rapid emergence of enfuvirtide resistance in HIV-1-infected patients: results of a clonal analysis.
OBJECTIVE
To study the dynamics of enfuvirtide (T-20) resistance development in HIV-1-infected subjects.


METHODS
Clonal analysis of gp41 sequences was performed on serial samples obtained from HIV-1-infected subjects with early virologic failure of T-20-based regimens.


RESULTS
Enfuvirtide resistance mutations at codons 36 to 45 in the first heptad repeat of gp41 emerged within 2 weeks in most subjects and were associated with the return of plasma HIV-1 RNA level toward baseline by weeks 4 to 8. Mutations at codons 36 (G36E, G36D, or G36S) and 38 (V38A, V38G, or V38M) were the most commonly detected resistance mutations at week 2. Mutations at codons 40 (Q40H) and 43 (N43D) were more prevalent at week 4 than at week 2 and seemed to emerge more slowly than mutations at codons 36 and 38.


CONCLUSIONS
The rapid emergence of mutations associated with T-20 resistance in the absence of a fully suppressive antiretroviral regimen demonstrates a low genetic barrier to resistance and underscores the importance of combining T-20 with other active drugs when constructing regimens for highly treatment-experienced patients.
Lu
Jing
J
Section of Retroviral Therapeutics, Brigham and Women's Hospital, and Division of AIDS, Harvard Medical School, Boston, MA, USA.
Deeks
Steven G
SG
Hoh
Rebecca
R
Beatty
George
G
Kuritzkes
Benjamin A
BA
Martin
Jeffrey N
JN
Kuritzkes
Daniel R
DR
D000595:Amino Acid Sequence; D003001:Cloning, Molecular; D017931:DNA Primers; D024882:Drug Resistance, Viral; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000187:drug effects / Q000235:genetics* / Q000627:therapeutic use; D023581:HIV Fusion Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D000077560:Enfuvirtide