Amprenavir mutations may significantly affect LPV resistance

Resistance, cross-resistance and viral fitness are issues that most HIV clinicians and researchers discuss every day.

These issues are not only important in planning regimens and understanding genotypic resistance testing, but are also important in planning salvage regimens that may successfully suppress HIV – although perhaps not to undetectable levels – and allow some immune reconstitution.

In a study published in AIDS investigators evaluated the effect of amprenavir (APV, Agenerase) -selected resistance mutations on protease inhibitor (PI) cross-resistance and HIV replication capacity or fitness. The HIV-1 variants were obtained from passage in increasing concentrations of APV, as well as 3’Gag/protease recombinants derived from them. The investigators found that these HIV-1 strains progressively accumulated mutations at protease codons 10, 46, 47, 50 and 84 as well as a p1/p6 cleavage site mutation at codon 449 in Gag.

The sensitivity of the HIV-1 strains to APV decreased with increasing numbers of protease mutations. Changes in the HIV-1 strains sensitivity to lopinavir/ritonavir (LPV, Kaletra) were found to parallel the changes in APV susceptibility. In fact, certain APV -selected mutants conferred greater than 10-fold cross-resistance to LPV, including a mutant with mutations 10F/46I/50V plus GagL449F (19-fold) and 10F/46I/47V/50V plus GagL449F (31-fold). Further, one resistant HIV-1 isolate, that had only two mutations (10F/84V) plus GagL449F, displayed a 7.7-fold increase in LPV IC50. Some cross-resistance to ritonavir (RTV, Norvir) and nelfinavir (NFV, Viracept) was also observed.

Replication capacity or fitness of these HIV-1 variants was also assessed. The replication capacity of viruses containing either 84V or 50V was found to be at least 90% lower the wild-type HIV-1 used as a reference. The order of relative replication capacity was wild-type > L10F > L10F/I84V > L10F/M46I/I50V > L10F/M46I/I47V/I50V.

The authors conclude, “These results indicate that until more comprehensive genotype-phenotype correlations between amprenavir and lopinavir susceptibility are established, phenotypic testing may be preferable to genotyping to detect cross-resistance, and should be considered when switching patients from a failing amprenavir-containing regimen. This study also provides data on the concordance of replication capacity measurements generated using rapid single-cycle growth and competition assays.” This study also indicates the potential complexity of the resistance that develops from antiretroviral usage, especially protease inhibitors, and that planning sequential changes in antiretroviral therapy – with the hope that resistance to one drug will not affect another – is difficult, unpredictable and ultimately unlikely to be successful.

Comment

Despite all of the currently available resistance data on protease inhibitors it still remains unclear if any advantage is to be gained by a particular order of sequencing.

All of the currently available PI’s are cross resistant to each other, this perhaps being a function of them all being structurally related peptidomimetic compounds. Search behind each sequencing argument and you will usually find some spin related to market positioning of a particular pharmaceutical companies product.