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  International AIDS Conference
July 13-16, 2003, Paris
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High Viral failure Rates with Abacavir/3TC/Tenofovir Once Daily Regimen
Reported by Jules Levin
  It appears that patients receiving this once daily regimen are showing high rates of viral failure or non-response during the early stages of two studies. In addition, patients failing the regimen in the studies are showing genotypic resistance. It is not yet understood why this has happened, but GlaxoSmithKline is stopping their study. It is recommended not to use this regimen until it can be discovered what is going on. There are 2 possible explanations that have been suggested. There could be some type of drug interaction between abacavir and tenofovir, although preliminary investigation so far has not confirmed this. A second possibility is regarding the common drug resistance mutatiions between the drugs: M184V is the 3TC mutation and K65R is the tenofovir mutation, but M184V and K65R are both associated with resistance to abacavir. Key researchers from both companies held a meeting today in Paris to discuss this development, and do not yet have a good grasp as to why the viral failures occurred. But it appears that this is a high priority for them, and they are investigating it.
A second study using this regimen is being reported at the IAS Conference reporting similar results. A pilot study of 20 patients was started to assess the potency and effectiveness of once daily abacavir/3TC/tenofovir in treatment-naive patients. Patients were considered to be non-responder/failing if there was no reduction in viral load of 2 log by week 8 and/or a rebound in viral load after initial suppression. 52% of patients had viral load rebound: 1 at week 4, 6 at week 8, and 2 at week 16. It was reported that patients were >95% adherent by pill count. Patients are showing genotypic resistance as well. Genotypic analysis showed the 3TC mutation M184V was present in 2 patients. M184V+K65R (Tenofovir mutation) was found in 1 patient, and resistance testing is pending for others.
In a pre-IAS Conference meeting, GlaxoSmithKline reported they have stopped a study using the regimen of once daily abacavir/3TC/tenofovir because of a high viral failure rate. 200 treatment-naive patients were randomized in study ESS30009 to abacavir/3TC/tenofovir or abacavir/3TC/efavirenz, also once daily. Shortly after the study started 49% of the 102 patients randomized to abacavir/3TC/tenofovir regimen had viral failure compared to 5% of the 92 patients in the other study arm of abacavir/3TC/efavirenz. The difference is highly significant (p<0.001). By week 8, 31% of the patients in the abacavir/3TC/tenofovir arm failed to achieve a 2 log drop in viral load from baseline and still had viral load above 50 copies/ml compared to 3% in the other treatment group. In addition, 8% in the abacavir/3TC/tenofovir arm vs 0% in the abacavir/3TC/efavirenz group still had a viral load that was 1 log above nadir on any subsequent visit.
In the GSK study there is genotypic resistance data available for 8 patients on the abacavir/3TC/tenofovir treatment regimen. 3 patients had the K65R/K (mixtures of WT and mutant) tenofovir resistance mutation. All of the 8 patients had the 3TC M184V mutation (full mutant, not mixtures). 4 patients did not have the K65R mutation. 2 patients had the V118I and K101Q mutations, respectively.
Again, it is recommended not to use the abacavir/3TC/tenofovir regimen until further notice.