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Fuzeon Resistance
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"Withdrawal of fusion inhibitors from a failing antiretroviral regimen results in reversion to enfuvirtide susceptibility"
ABSTRACT 8
Antiviral Therapy 2004; 9:S12.
GD Miralles1, T Melby1, R DeMasi1, Y Zhang1,
G Heilek-Snyder2 and M Greenberg1
1 Trimeris, Inc., Durham, NC, USA; and 2 Roche, Palo Alto, Calif.,
USA
BACKGROUND: In vitro growth competition assays and observations of decay of enfuvirtide-resistant viral populations after short-term monotherapy have suggested substantial decreases in fitness of enfuvirtideresistant variants. However, the dynamics of these populations after interrupting chronic enfuvirtide treatment have not been examined.
METHODS: Patients failing an enfuvirtide-containing regimen participated in a 10-day T-1249 replacement study (T1249-102). Subsequently, patients opted to resume or discontinue ENF while continuing their failing background regimen pending enrolment in a T-1249 chronic dosing study. We compared genotype (GT) in gp41 aa 36--45, and enfuvirtide phenotype (PT) from patients while on a failing enfuvirtide regimen (baseline, prior to T-1249) and after resumption or discontinuation of ENF following short-term T-1249 therapy.
RESULTS: Patients studied (n=18) had documented resistance to enfuvirtide and had been failing an enfuvirtide-containing regimen for a median of 61 weeks. Eight resumed enfuvirtide (Resumed) for a median of 82 days while 10 interrupted fusion inhibitors (FI, Interrupted) for a median of 114 days (range 46--230). At baseline, median HIV RNA and geometric mean (GM) change in enfuvirtide FCIC50 (normalized IC50) were 4.86 log10 copies/ml and 133.9-fold for Resumed patients and 4.98 log10 copies/ml and 120.5-fold for Interrupted patients. Relative to T-1249 baseline, at the end of the observation period HIV RNA did not change in Resumed patients (--0.05 log10 copies/ml) while it increased a median of +0.21 log10 copies/ml in Interrupted patients. Similarly, GM enfuvirtide FCIC50 increased 1.1-fold for Resumed while for Interrupted itdecreased by 10.0-fold (P=0.006). Decreases in enfuvirtide FCIC50 >10-fold were seen in 0/8 Resumed and 6/10 Interrupted patients; two Interrupted patients had changes between two- and 10-fold. The two Interrupted patients who showed no changes in enfuvirtide susceptibility were among those with the shortest interruption of FI (46--57 days). In Interruptedpatients, reversions to enfuvirtide susceptibility were generally associated with GT reversions.
CONCLUSION: Following chronic enfuvirtide treatment, interruption of FI resulted in replacement of FI resistant populations by more susceptible ones. These findings extend earlier observations that fitness disadvantagesobserved in ENF-resistant viruses in vitro result in parallel fitness disadvantages in vivo.
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