Interruption of Enfuvirtide in HIV‐1–Infected Adults with Incomplete Viral Suppression on an Enfuvirtide‐Based Regimen

Abstract

Many antiretroviral drugs continue to exert an anti-human immunodeficiency virus (HIV) benefit in the presence of drug resistance mutations. The degree to which enfuvirtide exerts continued antiviral activity in the presence of incomplete viral suppression has not been defined. To address this question, 25 subjects interrupted enfuvirtide while remaining on a stable background regimen. Enfuvirtide interruption was associated with an immediate but limited increase in plasma HIV-1 RNA levels. Enfuvirtide resistance waned rapidly in the absence of drug pressure and was no longer detectable by week 16 in most individuals. These data indicate that enfuvirtide has measurable antiviral activity in the setting of incomplete viral suppression. Although enfuvirtide resistance mutations are associated with significant fitness defects in vivo, the clinical significance of these mutations remains undefined.

Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness

“…Similar observations were made in nonrandomized studies of lamivudine or lamivudine-zidovudine interruption (28,59). Selective interruption of the fusion inhibitor enfuvirtide leads to prompt but limited increases in viral load (ϳ0.1 to 0.2 log 10 copies/ml), indicating that this drug also has some limited efficacy despite the presence of drug-resistant variants (39). These increases in viral load were not temporally associated with the loss of resistance mutations, suggesting that improvements in viral fitness were not driving these viral rebounds.…”

The fusion inhibitor enfuvirtide in recent antiretroviral strategies

“…Interruption of enfuvirtide in 22 patients experiencing virological failure under enfuvirtide and OBT for at least 24 weeks was associated with a small but statistically significant increase in plasma HIV-1 RNA levels [34]. This increase occurred immediately after interruption of enfuvirtide before any measurable change in genotypic or phenotypic resistance.…”

Partial treatment interruptions

“…A small but statistically significant increase in HIV RNA levels was observed in the first 1-2 weeks after removal of enfuvirtide ($0.2 log 10 copies RNA/ml), suggesting some residual antiviral activity [48]. In contrast with our experience with protease inhibitor and the non-M184V reverse transcriptase inhibitor mutations, enfuvirtide-associated mutations waned rapidly during the partial treatment interruption phase [48]. This loss occurred within 16 weeks and appeared to be due to continued viral evolution ('back-mutations') rather than rebound of an archived enfuvirtide-sensitive virus [61].…”