JAC Advance Access published online on August 5, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl306
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1 Department of Experimental Medicine and Biochemical Sciences, University of Rome, ‘Tor Vergata’, Rome, Italy; Department of Pharmaco-Biology, University of Calabria, Cosenza, Italy
* To whom correspondence should be addressed. Objectives: To investigate gp41 variability and correlation with viro-immunological parameters in 54 HIV-1-infected patients receiving enfuvirtide added as single active drug to a failing regimen. Methods: One hundred and two HIV-1 gp41 sequences and clinical follow-up from 54 enfuvirtide-treated patients were analysed from baseline to week 36 of treatment. The association of mutations with viraemia/CD4 count was assessed by Mann-Whitney test. Results: The addition of enfuvirtide to the failing regimen induced at week 4 a viraemia decrease from 5.1 to 4.3 log10/mL (P = 0.0002) and a CD4 increase from 48 to 106 cells/mm3 (P = 0.008). While viraemia rebounded to 4.8 and 4.6 log10/mL at week 12 and 36, respectively, CD4 continued to increase to 136 cells/mm3 at week 36. Enfuvirtide resistance mutations, rarely found at baseline, occurred in 45/54 (83.3%) enfuvirtide-treated patients. V38A/E were the most represented mutations at all time-points. The presence of V38A/E was significantly associated with a 4.5-fold CD4 increase from baseline to week 24 and with a 6-fold increase at week 36 (P = 0.004 and 0.02 compared without V38A/E, respectively), without significant correlation with viraemia. In contrast, Q40H + L45M (present in six enfuvirtide-treated patients at week 36) correlated with CD4 loss from baseline to week 36 (P = 0.02), without significant correlation with viraemia. Mutation N126K (observed in six enfuvirtide-treated patients, never found at baseline) abrogates the fourth gp41 glycosylation site and correlates with a 2.1-fold CD4 increase at week 24. Conclusions: Specific enfuvirtide resistance mutations (V38A/E) are associated with a sustained CD4 increase, without remarkable effects upon viraemia. This CD4 recovery, due to virus- and immune-mediated mechanisms most probably not applicable to protease/reverse transcriptase inhibitors, is important for innovative therapeutic strategies.
Received March 20, 2006
Revised July 4, 2006
Accepted July 6, 2006
Original article
Specific mutations in HIV-1 gp41 are associated with immunological success in HIV-1-infected patients receiving enfuvirtide treatment
Stefano Aquaro 1 * 
, Roberta D'Arrigo 2 , Valentina Svicher 3, Giovanni Di Perri 4, Sergio Lo Caputo 5, Ubaldo Visco-Comandini 2, Mario Santoro 3, Ada Bertoli 3, Francesco Mazzotta 5, Stefano Bonora 4, Valerio Tozzi 2, Rita Bellagamba 2, Mauro Zaccarelli 2, Pasquale Narciso 2, Andrea Antinori 2, and Carlo Federico Perno 2
2 National Institute for Infectious Diseases ‘L. Spallanzani’, Rome, Italy
3 Department of Experimental Medicine and Biochemical Sciences, University of Rome, ‘Tor Vergata’, Rome, Italy
4 Clinic of Infectious Diseases, University of Turin, Hospital ‘Amedeo di Savoia’, Turin, Italy
5 Hospital ‘SM Annunziata’, Florence, Italy
Stefano Aquaro, E-mail: aquaro{at}uniroma2.it
Abstract These authors contributed equally to this work.
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