July 9, 2001
Marty Markowitz from Aaron Diamond AIDS Research Center presented 48-week data from a phase II, open-label, randomized study regarding the use of tipranavir (TPV), a non-peptidic protease inhibitor that showed potent activity in vitro against protease inhibitor-resistant HIV. The 41 patients enrolled in the study had clinically failed two or more protease inhibitor-containing regimens but were NNRTI-naive. The mean baseline CD4+ cell count and viral load of the enrolled patients were approximately 300 cells/mm3 and 4.5 log10 copies/mL, respectively.
The patients were assigned to receive one of two TPV and low-dose ritonavir (RTV) regimens in combination with sustiva (efavirenz, EFV) and one new NRTI. The study started with all of the patients receiving TPV hard-filled capsules (HFC, 300mg), but all were switched to soft-gel capsules (SGC, 250mg), which improve absorption of TPV, when they became available. The patients were randomized to group A (n=19) and received TPV (HFC 1,200mg BID followed by SGC 500mg BID) plus RTV 100mg BID, EFV 600mg QD and one NRTI, or to group B (n=22) and received TPV (HFC 2,400mg BID followed by SGC 1,000mg BID) plus RTV (initially 200mg BID but changed to 100mg BID when TPV SGC were started) plus EFV 600mg QD and one NRTI.
Due to the small number of patients enrolled in this study, at the end of 48 weeks of therapy the two arms were statistically equivalent in most respects regarding virologic outcome. This relative statistical equivalence does not, however, necessarily mean that the success rates between the two arms were identical. The study used intent-to-treat, last observation carried forward (ITT) and as treated (AT) analyses. Depending upon the analysis used, the mean decreases in viral load for group A were between 2 and 2.5 log10 copies/mL and for group B were between 1.5 and 2 log10 copies/mL, with the as treated analysis significantly favoring group A (p<0.05). Group A had 93.8% and 78.9% and group B had 78.6% and 50% of patients achieve a viral load less than 400 copies/mL under AT and ITT analyses, respectively (p=NS). Group A had 81.3% and 68.4% and group B had 64.3% and 40.9% of patients achieve a viral load less than 50 copies/mL under AT and ITT analyses, respectively (p=NS). The mean CD4+ cell count increased by 183.7 cells/mm3 in group A and 149.1 cells/mm3 in group B. Finally, in a sub-analysis that evaluated group A patients only, the mean viral load decrease in that group did not appear to be dependent on whether there were 5 or less or greater than 5 PI mutations present at baseline. Both dosing regimens appeared relatively well tolerated with the primary adverse events likely related to TPV consisting of diarrhea (59%), headache (39%), nausea (31%), fatigue (29%), and vomiting (17%). Only two patients discontinued therapy due to an adverse event.
Although extremely limited, these data are encouraging regarding future salvage options. TPV appears to be an effective and relatively well-tolerated agent in protease inhibitor-salvage therapy, at least in NNRTI-naive patients started on EFV as part of the salvage therapy. Further data will be anxiously awaited since treatment of multi-drug resistant patients is a topic of increasing importance in HIV treatment.
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