13th International HIV Drug Resistance Workshop 8–12 June 2004, Tenerife Sur-Costa Adeje, Canary Islands, Spain

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 enfuvirtide-resistant 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 it decreased 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 Interrupted patients, reversions to enfuvirtide susceptibility were generally associated with GT reversions.

CONCLUSIONS: Following chronic enfuvirtide treatment, interruption of FI resulted in replacement of FIresistant populations by more susceptible ones. These findings extend earlier observations that fitness disadvantages observed in ENF-resistant viruses in vitro result in parallel fitness disadvantages in vivo.

PRESENTING AUTHOR: GD Miralles

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2004-06-08
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