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Education > Clinical Updates

Clinical Update #5 - News from the 47 ^th Interscience Conference on Antimicrobial Agents and Chemotherapy

Chicago, Illinois
September 17-20, 2007

Earlier studies using a limited number of laboratory and clinical isolates demonstrated that the HIV-1 protease mutation I50L confers resistance to atazanavir and susceptibility to other protease inhibitors (PIs). Prakash Sista from Virco Lab, in collaboration with colleagues from Virco and xLeo Inc, presented data at the 47 ^th Interscience Conference on Antimicrobial Agents and Chemotherapy that reported the prevalence of I50L through 2006 and characterized its contribution to PI susceptibility, using a large genotypic database of routine clinical samples obtained between 1999 and 2006. They found that since 2003 when atazanavir was approved, the prevalence of I50L increased from 0.01% to 0.7% in 2006. In addition, as reported previously, the presence of I50L is associated with increased susceptibility to PIs other than atazanavir in a variety of protease mutational backgrounds.

A total of 224,813 routine clinical isolates (excluding clinical trials) were examined and I50L was detected in 474 isolates (correspond to 380 unique mutation profiles). Of these, 457 and 41,001 samples with and without I50L, respectively (comprising 66 mutation profiles), had >1 concurrent primary PI mutation as defined by IAS-USA. There could be other secondary mutations present which were not considered in this analysis. A further selection of a minimum of >3 samples in each profile yielded 307 and 37,098 samples with and without I50L, respectively (n=31 mutation profiles).

• The median predicted fold-change value for each mutational pattern was determined both in the absence and presence of I50L using the virco ^® TYPE HIV-1 system (version 4.1).
   
• For each mutational profile, a ratio of the median predicted fold-change value (in presence of I50L: in absence of I50L) was determined for all PIs.
   - PIs analyzed: atazanavir/ritonavir, darunavir/ritonavir, amprenavir/ritonavir, indinavir/ritonavir, lopinavir/ritonavir, nelfinavir, saquinavir/ritonavir, and tipranavir/ritonavir.

As expected, the presence of I50L caused decreased susceptibility to atazanavir in all 31 mutational profiles analyzed (predicted fold-change ratio >1). In contrast, the majority of the mutational patterns demonstrated I50L-related higher susceptibility for the other PIs: amprenavir (25/31), darunavir (30/31), indinavir (31/31), lopinavir (31/31), nelfinavir (28/31), saquinavir (29/31). For tipranavir, only 13 of 31 mutational patterns resulted in higher susceptibility.

Clinical relevance for the median predicted FC value of each mutational pattern was provided by comparison to drug-specific Clinical Cutoff (CCO) values and three resistance categories (Maximal, Reduced, or Minimal Response). An evaluation of the I50L-related shifts in resistance categories revealed that a varied number of the mutational patterns (range: 6.5% for darunavir to 71% for atazanavir) caused a minor shift across one-resistance category. A major shift across two resistance categories was observed across a smaller range (12.9% for atazanavir to 3.2% for nelfinavir/ saquinavir. For comparison, a similar analysis of the sensitizing effect of the reverse transcriptase mutation M184V on sensitivity to zidovudine was evaluated. An examination of 566 mutational profiles in presence and absence of M184V revealed that while the presence of M184V caused a minor or one-category shift in sensitivity to zidovudine for 30% of the mutational profiles, no profiles showed a major or two-category shift in sensitivity (data not shown in poster).

Data from this analysis of a large database of routine clinical isolates extend and confirm previous observations on I50L-associated increased susceptibility of PIs other than atazanavir, including the previously uncharacterized PIs darunavir and tipranavir. If you are interested in viewing the complete poster, please click here.

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