February 11, 2003
Over the last two years, a number of trials have explored the idea of "simplification." The idea is to start with patients who are on a protease-containing regimen that is working well, and has resulted in good viral control, and to switch to a protease-sparing regimen. This approach is sometimes used in patients with abnormal lipids or body shape changes, or simply in anticipation of these kinds of problems.
Anticipatory switches aim to reduce the number of pills, reduce the number of doses, decrease side effects, or simply to avoid potential long term complication. By and large, these trials have shown that switching when the viral load is well controlled results in continued viral control and can decrease cholesterol and triglycerides. However, less has been reported about why switch strategies don't work, and what happens to viral resistance.
The NEFA trial was an important switch study, since it was large (498 patients), well designed and randomized. Patients who had been on a protease inhibitor-containing regimen for at least six months and had viral loads that were lower than the limits of detection were randomized to switch to either nevirapine (NVP, Viramune), efavirenz (EFV, efavirenz) or abacavir (ABC or ABV, Ziagen), all in combination with 3TC (lamivudine, Epivir) and d4T (stavudine, Zerit) or AZT (zidovudine, Retrovir). The primary outcome data has been presented at previous meetings and the overall success rate was similar. However, fewer patients in the NVP and EFV arms had viral breakthrough, and fewer patients in the ABC arm failed because of side effects. An important determinant was whether the patients had been on previous treatment with one or two nucleosides before the era of "HAART." Those who had been on previous suboptimal therapy and then started PI-based therapy did well if they switched to an NNRTI but had a higher rate of failure on ABC. Among those whose first regimen was the three drug PI-containing regimen, all three regimens maintained good viral control.
This study looked at those patients with virologic failure, and described the patterns of resistance. Fifty-one patients had virologic failure, 15 on NVP), 12 on EFV, and 24 on ABC. Thirty-nine of the 51 who had viral breakthrough had been previously treated. Sequence data was available for 31 patients. Nucleoside analogue resistance mutations (NAMS, aka TAMS and once called AZT resistance mutations) were common. They were seen in roughly half of the patients failing NVP and EFV and in 14/17(82 percent) of the ABC recipients. The number of NAMS was higher in the patients failing ABC. NNRTI-resistance changes were seen in 5/9 failing NVP, 4/5 failing EFV and 2/17 failing ABC (a bit surprising, but not an uncommon finding).
The resistance data from this study reinforced the primary message of the trial. Among patients who are on a first regimen containing a PI, who want to change to a PI-sparing regimen, either to prevent or reverse protease side effects, all three regimens are safe and effective. Each has potential advantages and limitations, but all are good choices. With newer formulations and once-a-day dosing, this can allow for much simpler regimens.
However, as seen with other trials, ABC, 3TC and a thymidine analog (such as in Trizivir) is more likely to fail in patients who have a history of extensive "suboptimal" nucleoside use before the era of triple therapy.
Hopefully, we are not making similar mistakes today to those we made in the mid 90s that will limit future options. Clearly the one thing that is a constant in the field of HIV is surprise.
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