Differing patterns of HIV protease mutations predict resistance to ritonavir-boosted atazanavir and to Kaletra (lopinavir/ritonavir), according to an analysis of treatment response in the BMS 045 study carried out by the US Food and Drug Administration, providing further information that will allow clinicians to select the more appropriate drug in highly treatment-experienced patients. The findings are published in the April 4th edition of the journal AIDS.
The study also identified the degree of reduced drug susceptibility (phenotypic resistance) associated with a poorer response to each drug.
The BMS AI424045 study compared atazanavir/ritonavir and lopinavir/ritonavir in protease inhibitor-experienced patients plus tenofovir and another nucleoside analogue backbone; a third arm of the study treated patients with atazanavir/saquinavir plus tenofovir and a nucleoside analogue, but this arm showed inferior efficacy.
The study demonstrated equivalent virologic efficacy over 96 weeks for atazanavir/ritonavir and Kaletra. The study also found a comparable decline in virologic efficacy between the two drugs if participants had four or more protease mutations.
However, previous reports have not been able to clarify whether different patterns of mutations influence the response to each drug. The US Food and Drug Administration set out to identify the differences between the two drugs in order to assist physicians and patients when choosing a protease inhibitor.
The 045 study population is described elsewhere. Resistance characteristics of the study population were as follows:
- 46% of isolates had reduced susceptibility to at least one protease inhibitor.
- 25% of isolates had reduced susceptibility to atazanavir.
- The proportion of patients sensitive to atazanavir or lopinavir was equivalent.
| Reduced response to either drug if one of following present | Response rate of | Response rate of | Response rate of | Reduced response if five or more of the following present |
| M36I | 30, 32, 36, 47, 47, 48, 50, 53, 54, 71, 73, 77, 82, 84, 88, 90 | |||
| M46I | M46I/V/L | M46 | ||
| I54V/L/M | I54 | |||
| A71V/T/I | ||||
| G73S/A/C | G73S/A/C | |||
| V82A/F/T/S/I | V82A/F/T/S/I | V82 | ||
| I84V | I84V | I84V | ||
| L90M | ||||
| *If M46 or V82 present with one other mutation, lopinavir response was 67% and 100% respectively | *Response to atazanavir reduced when compared to lopinavir if five of the above present | |||
Key distinctions
- The presence of the L90M mutation did not affect response to lopinavir/ritonavir as substantially as it did response to atazanavir/ritonavir
- L90M had a greater impact on atazanavir response in patients with three or more baseline PI mutations; there was no difference between atazanavir and lopinavir response when this mutation was present with one or two other primary PI mutations
- No patient with five or more primary PI mutations responded to atazanavir, whereas 28% of lopinavir-treated patients with five or more mutations had a virologic response
- Baseline changes at I54 or I84 affected lopinavir response regardless of the number of baseline PI mutations.
- Reductions in drug susceptibility greater than fivefold were associated with significantly greater reduction in response to atazanavir/ritonavir than to lopinavir/ritonavir (11% vs 27%).
Naeger LK, Struble KA. Effect of baseline protease genotype and phenotype on HIV response to atazanavir/ritonavir in treatment-experienced patients. AIDS 20: 847-853, 2006.
Johnson M et al. 96-week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures. AIDS 20: 711 – 718, 2006.