• Lack of Resistance to Boosted 908 Observed Through 48 Weeks of Therapy in Naive Subjects (Poster 558)
  Authored by R. Elston, S. MacManus, P. Yates, S. White, N. Richards, W. Snowden, M. Tisdale

It is important to understand which resistant mutations are present when patients break through on a new drug. The next protease inhibitor (PI) to be licensed will probably be 908, also known as fosamprenavir or GW433908, so learning more about the real-life resistance patterns is timely.

908 is a new and much improved version of amprenavir (APV, Agenerase). The absorbtion rate is dramatically better, and it is relatively free of gastrointestinal (GI) side effects, based on the trials that have been presented so far. It is formulated as a compact 700-mg tablet, a far cry from the bulky 150-mg capsules of amprenavir.

Two dosing regimens of 908 have been studied in naive patients. In the NEAT trial, 908 was given as 1,400 mg twice daily. In the SOLO trial, 1,400 mg of 908 were given with 200 mg of ritonavir (RTV, Norvir) once daily. In both trials, the comparison arm was nelfinavir (NFV, Viracept). The background nukes consisted of abacavir (ABC, Ziagen) and 3TC (lamivudine, Epivir).

In the NEAT study, among those who had virologic failure, about one third had protease mutations. The expected amprenavir resistance mutations were seen. Nucleoside resistance mutations, primarily M184V, were predominant.

The remarkable finding was from the SOLO study. Among 32 patients who had virologic failure on boosted 908, none had new protease resistance mutations. Four patients (17 percent of those who failed) had M184V. In three patients it was the only resistance mutation. In the other 28 patients no specific resistance mutations were seen.

In contrast, among 54 patients in the nelfinavir arm of SOLO who had virologic failure, 50 percent had protease resistance mutations. Thirty-one or 54 percent had M184V with or without other nucleoside mutations. Twenty-four patients had no resistance mutations.

What does this mean? Looking at the SOLO trial, it is clear that about the same number failed with no resistance mutations. It is likely that these patients were not taking any of their medications, or were taking very few. Fewer patients failed in the boosted 908 arm overall. Fewer failed with 3TC or abacavir mutations, and none failed with PI mutations. This is quite similar to what was seen with lopinavir/ritonavir (LPV/r, Kaletra) in naive patients in the 963 study, in which no PI mutations were seen in the patients failing lopinavir/ritonavir.

To me, this suggests that both boosted regimens are sufficiently potent in naive patients so as to make it very difficult for PI resistance mutations to occur. When the virus does break through, it is either due to nucleoside resistance, or poor adherence. This needs to be weighed when choosing an initial regimen. Boosted protease regimens in naive patients offer great potency, but at a higher risk of metabolic side effects than non-nucleosides. The lower rate of resistance is another factor to add to the equation.

While no studies have yet looked at boosted atazanavir (ATV, Reyataz) in naive patients, these studies are coming. Boosted atazanavir has few adverse effects on lipids, in contrast to lopinavir/ritonavir and, to a lesser extent, boosted 908. So, when boosted atazanavir is studied in naive patients, it will be interesting to see whether it, too, prevents the emergence of PI mutations.