GlaxoSmithKline has announced that it is terminating a 200 person study of the combination of abacavir, tenofovir and 3TC due to a high rate of viral failure after a 16 week interim analysis. The study, code named ESS30009, was comparing abacavir/3TC/tenofovir with abacavir/3TC/efavirenz, both once daily regimens, in treatment-naïve patients. Abacavir/3TC/tenofovir would have been an attractive once daily NNRTI-sparing regimen if it had showed equivalence to the efavirenz-containing regimen, but the early results once again confirmed the pole position of efavirenz in first-line therapy.
After just four weeks on treatment, 49% of the 102 patients randomised to abacavir/3TC/tenofovir were classified as virologic failures, compared to 5% in the abacavir/3TC/efavirenz (p
At week 8, 31% of the patients in the abacavir/3TC/tenofovir arm failed to achieve a 2 log drop in viral load from baseline or still had viral load above 50 copies/ml compared to 3% in the efavirenz group.
At this point, resistance data are available for only eight patients, but all samples contain the M184V mutation associated with 3TC resistance, whilst three had the K65R mutation associated with abacavir and tenofovir resistance.
It is unclear if failure in this study was driven by the common mutational pathway of tenofovir and abacavir (the development of the K65R mutation) or if this study reveals the potential weakness of 3TC when dosed once daily. Further resistance analysis will be needed to answer this question. A pharmacologic interaction between abacavir and tenofovir cannot be ruled out; the lower rate of K65R when compared with M184V in the early resistance samples would tend to support the view that there simply wasn't enough drug around to generate resistance. However, suggestions that this study reveals the inherent weakness of triple nucleoside therapy per se are probably wide of the mark; the failure rate seen in this study is out of all proportion to that seen in other studies
A similar finding was reported at last week’s Second International AIDS Society Conference in Paris, from a small pilot study conducted by Dr Peter Ruane in Los Angeles. Twenty treatment-naive patients commenced the regimen; after 16 weeks, 52% had experienced viral rebound despite >95% adherence.