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Resistance: Atazanavir, Atazanavir/rtv, and Kaletra--studies 043, 045
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Reported for NATAP by Graeme Moyle, MD
Chelsea & Westminster Hospital, London, UK
9th EACS Conference in Warsaw
Oct 29, 2003
The impact of baseline resistance mutations on the efficacy of atazanavir, ritonavir boosted atazanavir and ritonavir boosted lopinavir
Two randomised, comparative studies have evaluated the relative efficacy of regimens containing atazanavir versus Kaletra. In study 043, patients currently failing on a protease inhibitor based regimen were randomised to modify their nucleoside analogue backbone based on resistance test guidance and receive either atazanavir 400 mg QD (n=150) or Kaletra three capsules BD (n=150). In study 045, patients experienced with protease inhibitors were randomised to receive atazanavir 300 mg with ritonavir 100 mg QD (n=120) or Kaletra three capsules BD (n=123) on a NRTI backbone which included tenofovir and one other nucleoside analogue. The trough concentrations of atazanavir when given as 300 mg with ritonavir 100 mg are approximately threefold higher than trough concentrations of atazanavir given as 400 mg alone. Across studies patients had similar entry characteristics, CD4 at baseline ranged 261-317 cells/mm3 and viral load 4.14-4.47log. Data on the outcome of studies has previously been presented through week 24. In the 043 study the unboosted atazanavir resulted in a smaller decline in viral load (-1.67 log) than the Kaletra group (-2.11 log). After 24 weeks the study was ammended to allow patients to change regimens to one of several options, but very few did. The study was continued for 48 weeks. In the 045 study significant differences were not observed between the atazanavir group (mean decline in viral load -1.86 log) and the Kaletra group (-1.89 log). This study remains ongoing.
In both studies 043 and 045, an impact of the baseline protease inhibitor resistance mutations was observed on treatment efficacy over 24 weeks of follow-up . Protease inhibitor resistance mutations for this analysis were defined very broadly incorporating all of the protease resistance mutations listed in the Stanford database, a total of 46 protease mutations many of which (such as some of the nine listed at codon 63) are really natural polymorphisms. In the 043 study, atazanavir provided a similar mean week 24 change in viral load to that seen in the Kaletra group in individuals who had 0 or 1 PI mutations (for example, in persons with one PI mutations at baseline the mean decline in viral load at week 24 was 2.2 log and 2.03 log in the atazanavir and Kaletra groups, respectively), where the individuals with two or three mutations there was approximately a 0.5 log difference between the performance of atazanavir and Kaletra (for example, in individuals with three PI mutations at baseline the reductions in viral load were -1.75 and -2.29 for the atazanavir and Kaletra groups, respectively). For individuals with four or five mutations at baseline the difference in performance was even more marked (for example, in individuals with five mutations at baseline the reductions in viral load were -1.34 and -2.32 in the atazanavir/r and Kaletra groups, respectively).
In the 045 study, similar trends were observed. The atazanavir/r group tended to outperform the Kaletra group in individuals with 0 or 1 mutations (for example, in persons with one PI mutations at baseline the reduction in viral load at week 24 were -2.69 and -2.16 for the atazanavir/r and Kaletra arms, respectively). In individuals with two or three baseline mutations the Kaletra group tended to do a bit better (for example, for individuals with three baseline mutations the reductions in viral load were -1.75 and -2.02 in the atazanavir/r and Kaletra arms, respectively). In individuals with four or five baseline mutations Kaletra also tended to outperform atazanavir/r (for example, in individuals with five mutations at baseline reductions in viral load were -0.86 and -1.34 in the atazanavir/r and Kaletra groups, respectively). Similar observations were reported when the proportion of individuals achieving a viral load less than 400 copies/ml or less than 50 copies/ml at week 24 were considered.
Given the definitions of resistance used in this study there is insufficient information to define a genotypic cut-off that is clinically relevant for the relative loss of atazanavir effect. The data indicate that atazanavir or atazanavir/r perform as well if not better than Kaletra in individuals with 0 or 1 protease mutations at baseline and then forward suggest that atazanavir may be a preferred first protease inhibitor. As more mutations accumulate in the protease gene the performance of unboosted atazanavir and to a lesser extent the performance of boosted atazanavir tends to deteriorate whereas Kaletra tends to have greater effects on viral load in more mutated viruses. Previous data reported indicated that when atazanavir is used as first protease inhibitor, if resistance arises it is with a unique signature mutation (I50L), which may modestly increase virus susceptibility to Kaletra and other protease inhibitors.
More work on these databases is now required to more completely appreciate which mutations are important to the efficacy of atazanavir in practice. Physicians interpreting resistance tests require more detail than provided from the analysis presented at the ninth EACS to make decisions about the choice of atazanavir or atazanavir/r relative to Kaletra. |
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