Tipranavir / ritonavir (Norvir) is more effective than other commonly prescribed ritonavir-boosted protease inhibitors (PIs) in patients with extensive treatment experience, according to 24-week findings from the RESIST-1 study presented on Sunday at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Washington DC.
Tipranavir is a new PI developed by Boehringer Ingelheim that is dosed twice daily with 200mg of ritonavir. Tipranavir’s development programme has focused on its use in highly treatment-experienced patients, since patients with extensive experience of PIs have shown minimal reductions in susceptibility to the drug.
The RESIST-1 study was designed to compare the effect of tipranavir / ritonavir in comparison to other boosted PIs in patients effectively requiring `salvage therapy`.
Patients were eligible to enter RESIST-1 if they had at least three months experience of each of the three major drug classes and a resistance test showing evidence of at least one of the major PI resistance mutations from the group 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, 90M, or at least two of the mutations at codons 33, 82, 84 and 90. Participants had viral load above 1000 copies/ml, but there were no CD4 cell count entry restrictions.
The RESIST-1 study randomised patients to receive tipranavir / ritonavir plus a background regimen optimised by resistance testing (Trugene genotypic test) or a ritonavir-boosted PI (lopinavir, amprenavir [Agenerase], indinavir [Crixivan] or saquinavir [Invirase / Fortovase]). All participants were permitted to include T-20 (enfuvirtide, Fuzeon) in the background regimen.
RESIST-1 recruited 620 patients, and 311 were randomised to tipranavir, 307 to the optimised boosted PI regimen. The median CD4 cell count was 123 cells/mm3, and the median viral load was 64,600 copies/ml in the tipranavir group and 67,600 copies/ml in the comparator group. Participants had 15 baseline PI resistance mutations and had taken a median of 12 prior agents, with a median of six prior nucleoside analogues and four prior PIs.
After resistance testing, 61% of participants were assigned lopinavir / ritonavir (Kaletra) in their comparator regimen, 20% saquinavir / ritonavir, 14% amprenavir / ritonavir and 4% indinavir / ritonavir. Thirty-six per cent of all participants received T-20 in their regimen.
Baseline phenotypic susceptibility testing showed that whilst participants had a 77-fold reduction in susceptibility to lopinavir compared to wild type virus, susceptibility to tipranavir was reduced by 1.5-fold.
After 24 weeks of treatment, 263 patients in the tipranavir group were on treatment and 151 patients in the comparator group were still on treatment. Thirteen virologic failures occurred in the tipranavir group and 109 in the comparator group. Treatment failure was defined as a treatment change or a viral load reduction of less than 1.0 log10 at week 24. Twenty-five discontinuations due to adverse events occurred in the tipranavir group and nine in the comparator group.
By intent-to-treat (missing equals failure) analysis 42% of the tipranavir group had viral load below 400 copies/ml, compared to 22% in the comparator group (p
Amongst patients who received T-20 in their regimen, 47% of the tipranavir group and 22% of the comparator group achieved viral load below 400 copies/ml, and 33% and 14% below 50 copies/ml. The investigators noted that the presence of active nucleoside analogues and non-nucleoside reverse transcriptase inhibitors (NNRTIs) also improved the response, although data were not shown.
The only significant difference in adverse events was seen in elevations of the liver enzyme alanaine aminotransferase (ALT): 7% of the tipranavir group experienced grade 3 or 4 ALT elevations, compared to 1% of the comparator group (p = 0.001). Grade 3 or 4 elevations of cholesterol and triglycerides were also more common in the tipranavir arm.
Boehringer Ingelheim filed licensing applications for the United States and the European Union last week, and hopes to receive a United States license by May 2005, with a European license to follow by late summer. Data from a second study with a very similar design, called RESIST-2, will be presented at an international conference in Glasgow in mid-November.
Hicks C et al. RESIST-1: a phase 3, randomized, controlled, open label, multicenter trial comparing tipranavir/ritonavir (TPV/r) to an optimized comparator protease inhibitor/r (CPI/r) regimen in antiretroviral (ARV) experienced patients: 24 week data. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, abstract H-1137a, 2004.