Differing predictors of resistance to atazanavir/ritonavir or Kaletra identified

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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.

Glossary

protease inhibitor (PI)

Family of antiretrovirals which target the protease enzyme. Includes amprenavir, indinavir, lopinavir, ritonavir, saquinavir, nelfinavir, and atazanavir.

response rate

The proportion of people asked to complete a survey who do so; or the proportion of people whose health improves following treatment.

efficacy

How well something works (in a research study). See also ‘effectiveness’.

equivalence trial

A clinical trial which aims to demonstrate that a new treatment is no better or worse than an existing treatment. While the two drugs may have similar results in terms of virological response, the new drug may have fewer side-effects, be cheaper or have other advantages. 

nucleoside

A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

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%).
References

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.