Medical Advocates for Social Justice
Conference Abstract
from the
1st European HIV Drug Resistance Workshop
Cercle Municipal, Luxembourg

March 06- 08, 2003
 

 
Distinct cross-resistance profiles of the new protease
inhibitors (PI) Amprenavir, Lopinavir, and Atazanavir
in a panel of clinical samples [Abstract 1.11]
 
B. Schmidt 1,2, T. Schnell 1, G. Moschik, C. Thein,
 C. Paatz, K. Korn, H. Walter

 

1 University of Erlangen-Nuernberg, Erlangen, Germany,
2 University of California, San Francisco (UCSF), San Francisco, USA

  
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Background
PI-based regimens play an important role in the combination therapy of HIV-1 infected patients. However, PI use is limited due to high pill counts, variable oral bioavailability, and broad cross-resistance. These limitations may be overcome by new PI with favourable cross-resistance profiles and boosting of PI trough levels by low-dose Ritonavir. Recently, the new PI Amprenavir and Lopinavir have been approved, and Atazanavir will follow soon. Cross-resistance profiles of these drugs remain to be defined, and the effect of boosting on clinically relevant cut-offs is largely unknown.

Methods
A panel of 245 clinical samples was retrospectively evaluated, which were derived from 226 HIV-infected patients treated at more than 20 outpatient centres and private practices in Germany between 1/1998-7/2002. Samples were selected for availability of treatment histories; all patients were naïve for Amprenavir, Lopinavir, and Atazanavir. Resistance testing was performed by a recombinant virus assay.

Results
Reduced susceptibilities of more than 3.5-fold were observed for Indinavir (46.1%), Saquinavir (43.3%), Ritonavir (43.7%), Nelfinavir (51.0%), Amprenavir (33.1%), Lopinavir (36.7%), and Atazanavir (43.3%). 24.8% of the Lopinavir resistant samples ranged between 3.5- and 9.5-fold reduced susceptibility. If 9.5-fold reduced susceptibility was applied as cut-off, the number of Lopinavir resistant samples was reduced to 26.5%. Samples resistant against at least one of the previously approved PI frequently displayed cross-resistance to Atazanavir (78.3-85.5%), whereas cross-resistance to Lopinavir (62.0-75.0%) and in particular to Amprenavir (58.7-67.1%) was considerably lower. If 9.5-fold was used as cut-off for Lopinavir, cross-resistance was reduced to 44.6-53.9%. Similar results were obtained if cross-resistance to the new PI was evaluated with respect to the number of previously approved PI showing more than 3.5-fold reduced susceptibility and the number of PI in the pre-treatment. These data indicate a higher cross-resistance of Atazanavir compared to Lopinavir and Amprenavir. Furthermore, these data suggest that PI cross-resistance is considerably influenced by drug levels.

Discussion
The enhanced drug exposure by boosted PI may have three consequences: (i) clinically relevant cut-offs may be increased, (ii) low-level resistance may be overcome by boosted PI, and (iii) boosted PI may successfully be applied for salvage therapy.

Editor's Note:
Also refer to
Distinct cross-resistance profiles of the new protease inhibitors amprenavir,
lopinavir, and atazanavir in a panel of clinical samples.
 Schnell T, Schmidt B, Moschik , et al AIDS. 2003 May 23;17(8):1258-61.
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Distinct cross-resistance profiles of the new protease inhibitors (PI) Amprenavir,
 Lopinavir, and Atazanavir in a panel of clinical samples
1st European HIV Drug Resistance Workshop
A Medical Advocates for Social Justice Update