Atazanavir resistance: independent study finds high cross-resistance to atazanavir

Keith Alcorn
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This article is more than 22 years old.

German researchers have reported higher levels of reduced susceptibility to atazanavir in single protease inhibitor experienced patients than recently reported by the drug’s manufacturer, Bristol Myers Squibb (see previous news report). The new findings, published in the May 23rd edition of AIDS, are likely to increase curiosity about the resistance profiles of patients who benefited from atazanavir alone in the 043 study, or who experienced failure of ritonavir-boosted atazanavir in the 045 studies (see previous news report), since this information will help define the parameters within which ritonavir-boosted atazanavir is likely to be useful.

The new protease inhibitor atazanavir was recommended for US approval last week (see news report), but the US Food and Drug Administration has still to make a decision about what to say to prescribers and patients over its use in protease inhibitor-experienced patients.

The German group, based at the German National Reference Centre for Retroviruses in Erlangen, say that although their sample is relatively small, they were able to show that almost 40% of patients with experience of just one protease inhibitor already had reduced susceptibility to atazanavir (n=48), compared to 18% with reduced susceptibility to amprenavir and 12.5% to lopinavir boosted with ritonavir.

Glossary

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

sample

Studies aim to give information that will be applicable to a large group of people (e.g. adults with diagnosed HIV in the UK). Because it is impractical to conduct a study with such a large group, only a sub-group (a sample) takes part in a study. This isn’t a problem as long as the characteristics of the sample are similar to those of the wider group (e.g. in terms of age, gender, CD4 count and years since diagnosis).

protease inhibitor (PI)

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

cross resistance

The mechanism by which a virus that has developed resistance to one drug may also be resistant to other drugs from the same class. 

 

Food and Drug Administration (FDA)

Regulatory agency that evaluates and approves medicines and medical devices for safety and efficacy in the United States. The FDA regulates over-the-counter and prescription drugs, including generic drugs. The European Medicines Agency performs a similar role in the European Union.

In comparison BMS researchers found that less than 14% of patients with exposure to one or two prior protease inhibitors had reduced susceptibility to atazanavir. These isolates came from participants in clinical trials of atazanavir, whilst the German isolates came from patients with `known treatment histories`.

When samples with greater than 3.5-fold reduced susceptibility to approved protease inhibitors were tested for susceptibility to other PIs, atazanavir was amongst the most compromised agents, with 78% of nelfinavir-resistant isolates (n=92) also resistant to atazanavir, 85% of ritonavir-resistant isolates (N=76) resistant to atazanavir, 81% of saquinavir-resistant isolates (n=75) and 84% of indinavir-resistant isolates (n=81) resistant to atazanavir.

These isolates were less likely to show reduced susceptibility to lopinavir, with around half of isolates resistant to another agent still susceptible to lopinavir. Forty per cent of isolates showing reduced susceptibility to nelfinavir, ritonavir, indinavir and saquinavir remained susceptible to lopinavir when boosted with ritonavir (calculated using a susceptibility cut-off of 9.5-fold to simulate the effect of ritonavir boosting).

The findings add support to the view that ritonavir-boosting of atazanavir will be essential in PI-experienced patients.

Reference

Schnell T et al. Distinct cross-resistance profiles of the new protease inhibitors amprenavir, lopinavir and atazanavir in a panel of clinical samples. AIDS 17 (8): 1258-60, 2003.

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