July 9, 2002
It is important to understand what types of viral resistance develop after a regimen fails. Although we have been looking at resistance to nucleoside analogues for some 12 years, the complexity is astounding and we still have a lot to learn. The more complex the combination, the more we may learn about how the virus escapes our therapies.
NZTA 4008 was a trial of rescue therapy for patients failing their first regimen of zidovudine (ZDV), epivir (3TC) and one or two protease inhibitors (PIs). Patients were randomized to receive abacavir (Ziagen), efavirenz (Sustiva) and ddI (Videx) with or without hydroxyurea. The main trial results were presented earlier, and showed that hydroxyurea had a minimal benefit in lowering viral load, but at a cost of higher toxicity and lower CD4 count responses. This paper looked at the pattern of resistance mutations in those patients breaking through.
One might expect to see resistance to efavirenz, early resistance to abacavir (such as M184V), broad resistance to abacavir (multiple TAMs -- thymidine analogue mutations, a.k.a. NAM or NEMS), or resistance to ddI. Perhaps the biggest risk might be that broad multi-drug resistance might emerge.
At study entry, 90 percent of patients had mutations conferring resistance to PIs. Seventy-six percent had both PI mutations and some mutations associated with nucleoside resistance. Those who had the v mutation and at least three TAMs had a much higher failure rate. The presence of M184V alone did not change the response rate.
The majority of patients acquired new mutations when they failed. The majority (8/10) acquired new resistance to NNRTIs such as efavirenz. The most common mutation was the K103N mutation, which leads to resistance to the whole class of NNRTIs. Six to ten developed the L74V mutation which leads to ddI resistance.
This study is interesting for several reasons. First, it confirms that abacavir remains useful in patients with the M184V mutation and one or two TAMs, but looses effect when there are three or more TAMs. Secondly, it showed that both ddI and NNRTI mutations contributed to treatment failure. Third, it showed that hydroxyurea did not change the pattern of resistance. Lastly, it showed the deep hole that a patient can be left in if they develop resistance to all three classes of available agents.
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