title: Continued evolution in gp41 after interruption of enfuvirtide in subjects with advanced HIV type 1 disease.
abstract: Careful examination of viral dynamics during antiretroviral treatment can provide important insights into HIV pathogenesis. We examined viral evolution during and after enfuvirtide (T-20) treatment with an objective of defining the characteristics of viral evolution during advanced HIV immunodeficiency. Specifically, we examined the viral quasispecies from nine patients who experienced incomplete viral suppression on an enfuvirtide-based regimen, and who subsequently interrupted enfuvirtide while remaining on a stable optimized background regimen (enfuvirtide "partial treatment interruption"). On average, eight clones were sequenced from three time points: pre-enfuvirtide, post-enfuvirtide failure, and post-enfuvirtide interruption. We utilized a Bayesian hierarchical phylogenetic model to assess the evolutionary relatedness of the virus that emerged over time. In most subjects, interruption of enfuvirtide was associated with continued viral evolution as enfuvirtide mutations waned; in no subject did we find clear evidence supporting the reemergence of archived wild-type variants (Bayes factor=30.2, p=0.01). Evidence supporting ongoing viral evolution was particularly strong in subjects whose virus remained diverse or became more diverse during enfuvirtide therapy. In contrast to observations when all drugs are interrupted, loss of resistance during enfuvirtide interruption is most likely due to ongoing viral evolution (and back-mutation), rather than emergence of an archived virus.
authors.affiliation: Department of Biostatistics, University of California, Los Angeles, Los Angeles, California 90095, Section of Retroviral Therapeutics, Brigham and Women's Hospital, Boston, MA 02115, USA. cr@ucla.edu
authors.forename: Christina M R
authors.initials: CM
authors.lastname: Kitchen
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.forename: Marc A
authors.initials: MA
authors.lastname: Suchard
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hoh
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Martin
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Kuritzkes
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
mesh_terms: D001499:Bayes Theorem; D004334:Drug Administration Schedule; D024921:Drug Resistance, Multiple, Viral / Q000187:drug effects / Q000235:genetics; D000077560:Enfuvirtide; D019143:Evolution, Molecular; D015700:HIV Envelope Protein gp41 / Q000235:genetics* / Q000494:pharmacology; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics*; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology*; D010802:Phylogeny; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D000077560:Enfuvirtide