July 14, 2003
There are many HIV patients now who have multi-drug resistant virus and/or medication intolerances and face few viable treatment options. New medications are urgently needed to fill this treatment gap. One candidate agent moving through clinical trials and coming closer to approval is the protease inhibitor (PI) tipranavir (TPV) boosted with low-dose ritonavir (RTV, Norvir).
This new presentation on tipranavir/ritonavir (TPV/r) was an expanded analysis of data obtained in the phase II trial previously reported at the February 2003 Retrovirus meeting held in Boston (for previous reports, click here). In the original study (BI 1182.52), patients had to be triple-class experienced and failing therapy on a PI-based regimen. Additionally, they had to have at least one primary resistance mutation to a PI, but not more than one of the 82L/T, 84V or 90M mutations (these mutations are sometimes called UPAMs, or universal protease inhibitor associated mutations). TPV/r was substituted for the PI and following two weeks of functional monotherapy, the background regimen was optimized.
There is not a clear consensus on PI gene mutation terminology. The acronym PRAM has also been used to describe a set of mutations responsible for much of the cross resistance among PIs. PRAM stands for protease inhibitor-resistance associated mutations and consists of L33W/F, V82A/F/L/T, I84V and L90M. In most cases, the presence of one or two PRAMs is associated with reduced sensitivity to currently available PIs.
In this analysis, the virologic response from the two-week TPV/r functional monotherapy was assessed based on baseline genotypic and phenotypic sensitivity tests. These data were also organized based on the three different dosages originally studied (500 mg/100 mg, 500 mg/200 mg and 750 mg/200 mg). Based on the results of this phase II trial, the dose of 500 mg/200 mg was selected for the pivotal phase III trials that are well underway.
The result of this analysis was that TPV/r had robust antiviral activity with an approximate 1 log reduction in HIV-RNA levels at two weeks when up to 20 baseline PI gene mutations were present. The virologic response based on the number of PRAMs present was also calculated:
The impact of PRAMs on baseline phenotypic testing was also presented. The apparent cut-off for phenotypic resistance for TPV/r is a two-fold change in IC50. In this analysis, the median fold change in TPV/r IC50 was less than two for isolates with two or fewer PRAMs. The median fold change for three PRAMs was 2.2 fold, indicating probable resistance. This analysis shows that the number of baseline PRAMs appears to have predictive value when compared with both genotypic and phenotypic testing results.
This study was presented by investigators from UCLA in Los Angeles and sponsored by Boehringer-Ingelheim, the maker of TPV/r.
Studies like this lay the groundwork for the determination of the clinical cut-offs for resistance testing. The correlation between total number of PI gene mutations and PRAMs may also add to the predictive value of baseline resistance testing for these multi-drug resistant viral isolates. TPV/r is currently being tested in pivotal phase III trials and will become available on a limited basis through expanded access in the near future as these trials complete enrollment.
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