Report 11 -  4th International Workshop on HIV Drug Resistance and Treatment Strategies
Written by Jules Levin
Sitges, Spain, June 12-16 2000

ABT-378 (Kaletraô): Preliminary Resistance & Cross-resistance

BRIEF SIMPLE SUMMARY OF REPORT

This laboratory study reported at the Resistance Workshop in Spain suggests that individuals who have resistance to protease inhibitors and have ABT-378 resistance may respond to tipranavir, amprenavir, and saquinavir. Tipranavir is a new protease inhibitor being developed just to treat individuals with resistance to protease inhibitors. Information was reported at the Workshop in Spain suggesting that tipranavir should be effective for individuals with resistance to protease inhibitors. However, all of this information should be kept in perspective. Although this information is promising, the information is based on preliminary laboratory research. It needs to be confirmed in human studies. Individuals with ABT-378 resistance need to be given tipranavir to see if they will respond to tipranavir. Until we have that kind of study this information is interesting but preliminary.

In a small study Abbott researchers looked at phenotypic resistance to ABT-378 for 3 individuals who had used ABT-378 and had detectable HIV viral. They had 4 to 112-fold resistance to ABT-378 and had pre-existing resistance to other protease inhibitors. With test tube (in vitro) testing, they found that all 3 had no resistance or demonstrated modest resistance to amprenavir (8.5 fold resistance) while they had 99-resistance to ABT-378; 2 of the 3 individual's who had no prior saquinavir experience had no resistance to saquinavir; a virus that was created to be resistant to ABT-378 in the lab (34 fold resistant to ABT-378) had no resistance to tipranavir; 3 isolates tested against tipranavir were fully sensitive.

Genotypic and phenotypic analysis of viral isolates from subjects with detectable viral load on therapy with ABT-378/ritonavir

Akhter Molla from Abbott Labs reported on a small study looking at the emergence of resistance to ABT-378, whose brand name is Kaletra. Four naÔve and 8 PI experienced subjects were identified in whom viral rebound >1000 copies/ml occurred during ABT-378 treatment. Paired baseline and rebound patient viral isolates were characterized genotypically and phenotypically, using genotypic sequencing and Antivirogram (Virco) or PhotoSense (Virologic) phenotypic testing.

Among isolates from the 4 treatment naÔve subjects, all of whom were poorly adherent, none demonstrated ABT-378 resistance at rebound. The lack of detectable resistance could be because the patients were not adherent or, as has been reported in other studies, initial resistance upon rebound is sometimes found to be 3TC resistance but not PI resistance. Isolates from the other 4 PI-experienced subjects had „4 protease mutations at baseline and evolved 1-3 additional mutations during rebound (from among positions 24, 33, 36, 46, 54, 63, 71, and 82). This was associated, in 3 subjects, with a further decrease in ABT-378 or Kaletra susceptibility  (4- to 112-fold) compared with the corresponding baseline virus (one rebound isolate could not be grown for determination of phenotypic resistance). Relative to wild-type HIV, median ABT-378 susceptibility was reduced 33.6-fold for these 3 rebound isolates. However, Molla reported that all 3 remained fully sensitive or demonstrated modestly reduced susceptibility (up to 8.5 fold) to amprenavir, while they were 99-fold resistant to ABT-378; 2 of 3 isolates from individuals who never before had saquinavir remained fully sensitive to saquinavir; and 3 isolates that were tested against tipranavir were fully sensitive, as was a strain produced by in vitro passage with ABT-378. The strain was 34-fold resistant to ABT-378 and 0.9-fold (no resistance) to tipranavir.  I think individuals who develop resistance to ABT-378 will have to be studied with tipranavir to see if they can respond to a tipranavir based regimen. This is an important study that will eventually have to be conducted.

Again, this information is very preliminary and needs to be tested in human studies to see if individuals with ABT-378 resistance will be responsive to tipranavir.