Susceptibility to saquinavir and atazanavir in highly protease inhibitor (PI) resistant HIV-1 is caused by lopinavir-induced drug resistance mutation L76V

Poster number: 28

S.M. Mueller(1), M. Däumer(2), R. Kaiser(2), H. Walter(1), R. Colonno(3), P. Braun(4), K. Korn(1)

  1. Institute for Clinical and Molecular Virology, Erlangen, Germany
  2. Institute for Virology, Cologne, Germany
  3. Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut, USA
  4. PZB Aachen, Germany

Background: Samples from seven patients were susceptible to saquinavir and atazanavir despite resistance to all other PI. Genotypically, all samples were expected to be resistant to all PI, indicating a new resensitization mechanism in highly PI-resistant viruses.



Methods: Genotypic and phenotypic drug resistance were determined by sequencing (Viroseq) and by a recombinant virus assay, respectively. Sequence alignment has been performed to identify unique mutational patterns. The geno2pheno database and 246 samples from the BMS-045 study were screened for mutations identified in the first seven samples. Previous samples and clinical follow-up data were analyzed.



Results: All seven samples had 5-10 drug resistance associated mutations. All samples had mutations at codon 82 and mutation L76V, which has only been reported to be selected by lopinavir in vitro. 3/5 patients with available drug histories had been treated with lopinavir, one with lopinavir and indinavir, and one with amprenavir. L76V was not present in any other sample of the geno2pheno database, but in 11 patients from the BMS-045 study; nine of them developed L76V during lopinavir treatment. Phenotypic resistance of L76V samples to atazanavir and saquinavir ranged from 0.4-52-fold and 0.3-19-fold (median 2.3- and 1.7-fold), respectively. Only two samples exhibited >10-fold resistance to atazanavir (51-fold) and saquinavir (19-fold) despite L76V. They carried additional ten and eleven other mutations including V32I and V77I, which were not present in other L76V harbouring viruses. Clinical response data of three patients, who had been treated with saquinavir or atazanavir containing regimen, showed viral load decreases of >2.2log, >2.3log, and 3.1log within 12 weeks, receiving one, three and three active drugs, respectively.



Conclusions: L76V was not seen previously in clinical samples and seems to revert resistance to saquinavir and atazanavir in viruses with high level PI resistance. The mutation was mainly selected by lopinavir and was detected in 7% of patients in the lopinavir arm of BMS 045 study. Resensitization was highly clinically relevant in all three cases with follow-up. Therefore, the presence of L76V provides unexpected salvage therapy options. Further studies are needed to investigate high level resistance to atazanavir and saquinavir despite the presence of L76V.