December 18, 2001
When a person fails an initial protease inhibitor-containing regimen, the current thinking is to either use a NNRTI, or a boosted-protease inhibitor with two new nucleosides. With the increasing understanding of the degree of cross resistance among nucleosides, it has become more complex to try and define the new nucleoside backbone. This is particularly important when using an NNRTI because of the relative ease with which resistance develops with a non-suppressive regimen. With the licensing of abacavir, a new option became available, but most of the development was done with other products from the same manufacturer, GlaxoSmithKline. Clinicians have been eager to learn about the utility of abacavir with other nucleosides.
This study approached some of those questions by studying the use of abacavir, ddI and efavirenz in patients who had failed a first protease inhibitor-containing regimen. The regimen had to be either AZT and 3TC or d4T and 3TC with one or two protease inhibitors. The other aspect of this study was to explore the utility of adding hydroxyurea. This was an important question at the time the study was enrolling; since then hydroxyurea has fallen out of favor because the increased toxicity seems to outweigh the benefits, especially now that newer options are available. However, there is laboratory evidence that hydroxyurea may increase the efficacy of abacavir as well as ddI, so this study was based on a sound concept.
It was a small study; 54 patients were enrolled. They were randomized to receive abacavir, efavirenz and ddI with or without hydroxyurea 500 mg BID. Of the 54, 24 did not finish the study (10 in the ABC/EFV/ddI and 14 in the hydroxyurea-containing arm). One person in the no-hydroxyurea arm and seven in the hydroxyurea arm withdrew because of adverse events. Five patients in the no-hydroxyurea arm and one in the hydroxyurea arm had protocol-defined virologic failure.
With large rates of drop outs, we can expect a big difference between the ITT-M=F analysis and the as-treated analysis. Indeed, this was the case. There was no difference in virologic efficacy by ITT-M=F analysis. In the no-hydroxyurea arm, 58% were below 400 copies compared to 57% in the hydroxyurea arm by ITT-M=F at 24 weeks. Using the less than 50-copy assay, 50% in the no-hydroxyurea arm and 47% in the hydroxyurea arm were below the limit of detection.
In contrast, there was a trend favoring the hydroxyurea arm by as treated analysis. At 24 weeks, 67% were below 400 copies in the no-hydroxyurea arm compared to 89% in the hydroxyurea arm (p=0.008). There was less difference using the less than 50-copy endpoint: 57% vs. 74% (p=0.30).
As expected, the increases in CD4 count were excellent in the no-hydroxyurea arm: approximately 100 cells at week 48. In the hydroxyurea arm, there was very little improvement in CD4 count. Interestingly, in a subgroup where hydroxyurea was added after eight weeks, the increase in CD4 count was equivalent to the no-hydroxyurea arm.
Side effects were as expected, with central nervous system (CNS) symptoms common in both arms, and increased fatigue and gastrointestinal (GI) side effects in the hydroxyurea arm. There were no episodes of grade 3 or 4 hematologic toxicity. One case of pancreatitis occurred in the hydroxyurea arm, and neuropathy seemed to be more common in the hydroxyurea arm.
What can we conclude from this small trial? First, abacavir and ddI can be used safely together. Second, the backbone seems reasonably effective in patients with first failure when combined with efavirenz, but the small numbers and lack of resistance data limit our confidence in how effective this may be compared to other regimens. However, additional trials using abacavir and ddI after failure of a thymidine analogue plus 3TC regimen would be very useful.
Lastly, the conclusions about hydroxyurea are similar to other trials. There is a modest virologic benefit, offset by the increased toxicity. The toxicity includes both annoying and potentially dangerous ones. My feeling is that hydroxyurea no longer has a significant role due to its toxicity, but the strategy of using ribonucleotide reductase inhibitors might deserve more investigation with less toxic compounds.
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