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Kaletra resistance: hard to find in first line and second line use
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Written for NATAP by Graeme Moyle, MD, Chelsea & Westminster Hospital, London, UK
Resistance evolution with protease inhibitors is an interesting phenomenon. Different resistance patterns may arise at different drug exposures and with different viral clades. Additionally, resistance to protease inhibitors seems to arise more slowly than resistance to NNRTIs despite the fact that both groups of agents apply approximately the same selection pressure (as measured by drop in viral load after initiation). This is most likely to be because the impact of protease inhibitor resistance mutations on viral fitness is greater. Most intriguingly, several studies have now indicated that during use of boosted protease inhibitors in individuals previously naive to treatment, resistance to the protease inhibitor is not found at the time of viral rebound. Furthermore, the presence of a boosted protease inhibitor appears to delay the emergence of resistance to the nucleoside analogue drugs in the combination relative to the use of either an unboosted protease inhibitor or an NNRTI. This phenomenon has been reported during trials of boosted lopinavir and boosted fos-amprenavir. The search for resistance to boosted lopinavir (Kaletra) in initial therapy goes on.
Investigators from Abbott laboratories described the results of studies looking at emergence of resistance to Kaletra (or lack thereof) in individuals initiating Kaletra both when naive to antiretroviral therapy and when already experienced to other protease inhibitors. The studies are known as the SOKRATES trials. Both studies are prospective, open-label, multicenter studies evaluating genotypic and phenotypic resistance to Kaletra following confirmed viral rebound or lack of suppression (HIV RNA >1000 copies/mL) after a minimum of 16 weeks of Kaletra exposure as either initial (SOKRATES I) or second (SOKRATES II) PI-based therapy. To be defined as the typically resistance to lopinavir viral isolates were required to demonstrate a >10 fold reduced LPV susceptibility.
The preliminary results presented at the 9th EACS for patients screened for SOKRATES I and SOKRATES II. Previously data on over 500 patients exposed to Kaletra as initial therapy have been reported, with no evidence of resistance found. None of the patients screened for SOKRATES I had evidence of phenotypic resistance to lopinavir. In SOKRATES II eight patients were found to have phenotypic resistance to Kaletra. Only one individual in SOKRATES II has received a rescue regimen thus far. Of interest, this individual has a viral load <50 copies/ml after 24 weeks of SQV/r based regimen.
The observed rate of lopinavir resistance (with 99% confidence intervals (CI)) have been estimated from the samples used in the SOKRATES studies and the phase II/III development programs for Kaletra. The results are; Kaletra as First PI SOKRATES I 0/703 (0%) CI 0%-0.8%
Kaletra as First PI Phase II/III 0/508 (0%) CI 0%-0.9%
Kaletra as Second PI SOKRATES II 8/609 (1.3%) CI 0.4%-3.0%
Kaletra as Second PI Phase II/III 12/218 (5.5%) CI 2.3%-10.8%
The data indicate that the emergence of resistance to Kaletra is an infrequent event both when Kaletra is used as a first protease inhibitor or after failure of initial PI. Given the evidence from studies with unboosted protease inhibitors (such as the atazanavir data presented at this meeting, see separate report on NATAP) maybe less effective than Kaletra in individuals who are a previously exposed to protease inhibitor therapy or have established protease inhibitor resistance mutations, these data on lopinavir resistance may argue for the use of Kaletra as a second line protease inhibitor after the use of a more convenient initial PI.
Reference: Cernohous P, King M, Kempf D, et al. CHARACTERIZING EVOLUTION OF PROTEASE INHIBITOR (PI) RESISTANCE DURING LOPINAVIR/RITONAVIR (LPV/R) TREATMENT AND STUDY OF THE SALVAGE OF LOPINAVIR RESISTANCE (SOKRATES TRIALS) Abstract 3.1/2.
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