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To analyse the genetic changes in the gp41 protein in HIV-infected patients with detectable plasma viraemia receiving a long-term salvage enfuvirtide regimen.We studied 13 heavily antiretroviral-experienced patients receiving a salvage regimen containing enfuvirtide. Substitutions in gp41 were analysed by population-based sequencing at baseline and longitudinally after the initiation of enfuvirtide treatment. To investigate sequence evolution we also analysed multiple gp41 clones from four selected patients. A Fisher's two-tailed test was used to assess the distribution of resistance-associated mutations in the clonal sequences.Mutations at positions 36 and 38 in gp41 (HR1) emerged rapidly (median emerging time 10 weeks), but disappeared at subsequent timepoints in most of the patients. Amino acid changes did not accumulate over time, with no patient having more than two mutations in HR1 after 6 months of treatment. The mutation N43D was not observed together with changes at positions 36 or 38 in any patient. Clonal analysis showed that the three main gp41 resistance mutations were highly mutually exclusive (P < 0.001), being present in individual clones and constituting independent populations.Substitutions at positions 36 and 38 are rapidly selected but disappear thereafter in HIV-1-infected patients failing an enfuvirtide-containing salvage therapy. We found a highly exclusive relationship between the three main enfuvirtide resistance-associated mutations (amino acids 36, 38 and 43), suggesting that the genetic evolution of HIV-1 gp41 protein is a dynamic and much more complex process than previously though.