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Tipranavir Phase III Study Results
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Reported by Jules Levin
--Tipranavir shows potent antiviral activity in this study, and is an important drug for patients with extensive HIV drug resistance; but it is crucial to use it in combination with at least one additional HIV drug to which a patient is very sensitive to, such as Fuzeon. In this study patients who used tipranavir plus Fuzeon had the best results--
With great anticipation, results from the two large-scale phase III tipranavir study were reported at the USA conference ICAAC in October and today November 18 at Europe's AIDS Conference in Glasgow. For several years patients have had to wait for what was expected to be an important drug for patients with resistance to other PIs. Development of tipranavir was particularly slow due to the protease inhibitor drug being sold from one company, Pharmacia & Upjohn, who was leaving HIV to an active HIV drug company, Boerhinger Ingleheim. P & U did a poor job of conducting the preliminary studies needed for later stages of development, so BI had to redo studies when they acquired tipranavir. I remember well attending community meetings with P & U to discuss the very early data on tipranavir.
Finally, the results are in, and as expected tipranavir has potent antiviral activity against HIV with extensive resistance to currently available protease inhibitors. In this study, patients had their phenotypic resistance (Virco assay) to protease inhibitors evaluated before receiving tipranavir and it was found that as a group they had 104-fold resistance to Kaletra, 45-fold resistance to indinavir, 15-fold resistance to saquinavir, 11.8-fold resistance to amprenavir, 50-fold resistance to nelfinavir, 300-fold resistance to ritonavir, and 45-fold resistance to atazanavir. But patients had only 1.4-fold resistance, thus no resistance, to tipranavir.
Study patients who received tipranavir achieved a potent 1.6 log reduction in HIV viral load at week 4 after initiating tipranavir-based therapy. By week 24 the viral load reduction for these same patients was a median -0.72 log reduction from baseline. Thus viral load had rebounded some. This is likely due to study patients having some degree of resistance to most other drugs available to combine with tipranavir in the study. For patients who added Fuzeon (T-20) to their regimen in combination with tipranavir they had a significantly better response. This raises an important point. When starting a regimen with tipranavir, or when starting any new regimen, it is crucial to sustaining a good response to include other drugs in the regimen to which the patient has good sensitivity. Being that Fuzeon is a fusion inhibitor and a new class of drugs patients who have never before used it should be fully sensitive to the drug.
Pedro Cahn reported 24-week results from RESIST-2 in rainy Glasgow. Patients enrolled in this study had extensive resistance to HIV drugs. Patients were required to enter the study to have had at least 2 PI regimens one of which must have been their regimen just prior to this study. Patients were required to have at least one primary PI mutation at codons 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, or 90M. But patients were not permitted in the study if they had too much PI resistance because prior studies found that patients with more than 2 of mutations at these codons were not very responsive to tipranavir: 33, 82, 84, or 90. So patients who wanted into the study were not allowed if they had more than 2 of these mutations. Although, tipranavir has potent antiviral activity for many patients, for patients with a a certain high degree of PI resistance may not be able to mount a good response to this drug. As mentioned studies have found that patients with more than two of these key PI mutatins are not able to respond well to tipranavir.
In this study Treatment Response was defined as 1 log or more reduction in viral load from baseline at week 24. Resistance testing was used to select other drugs patients received in their regimens. Patients were randomized to receive a TPV based regimen or a Comparator PI regimen (CPI). All patients received an optimized background regimen. Study investigators could request guidance from an expert resistance panel in selecting drugs for a patient's regimen. After 8 weeks in the study patients without a Treatment Response in the CPI arm could request to receive TPV in a rollover study. The choices for the CPI arm were: Kaletra, IDV/r, SQV/r, and APV/r, all ritonavir boosted PIs.
Average age of study patients was 41 yrs, about 82% were men, 72% were white, and 15% had hepatitis C or B. The median CD4 count of participants was 185 and HIV viral load was 4.77 log. Patients had extensive prior treatment experience: median prior 12 ARVs (6 NRTIs, 1 NNRTI, and 4 PIs).
38% of patients received Kaletra, 2.6% indinavir/r, 20% saquinavir/r, and 40% amprenavir/r. 11.5% of patients also used Fuzeon. 30% of patients remained on the PI regimen they were taking before the study.
863 patients were treated in the study. 539 patients were part of the 24-week analysis. Through week 8, 17 patients in the TPV group discontinued therapy by week and 29 discontinued in the CPI arm. Through week 24, 50 on TPV discontinued and 125 discontinued from the CPI arm. 5 patients on TPV discontinued due to viral failure and 71 in the CPI arm discontinued due to viral failure.
RESULTS
At week 24, 41% of patients receiving TPV had a Treatment response compared to 14.9% in the CPI arm (ITT: non-completer=failure) (p<0.001). At week 4 viral load reduction was -1.5 log from baseline for patients taking TPV, and at week 24 their viral load reduction was -0.72 log from baseline. Patients in the CPI arm had -0.22 log reduction in viral load. (p<0.0001)
33% of patients receiving TPV & 13% of patients receiving CPI had <400 copies/ml viral load at week 24 9p<0.0001). 22% receiving TPV & 8.6% receiving CPI had <50 copies/ml viral load at week 24 (ITT: NC=F) (p<0.0001). However, use of Fuzeon increased response substantially. 38% of patients receiving TPV & Fuzeon had <400 copies/ml VL compared to 13% of patients receiving CPI+Fuzeon. 23% of patients receiving TPV+Fuzeon had <50 copies/ml at week 24 compared to 4.3% of patients receiving CPI+Fuzeon. Patients receiving TPV had increase of 31 CD4s at week 24 compared to a 1 cell increase for patients receiving CPI regimen. (p<0.022)
When examining grade 2-4 adverse events, patients receiving TPV compared to patients receiving CPI had more nausea (5.7% vs 2.8%), and more bronchitis (3% vs 0.7%). Overall, 49.9% of patients receiving TPV had grade 2-4 AEs compared to 46.5% of patients receiving CPI regimen. Patients receiving TPV were more likely to have grade 3-4 ALT elevations: 5.2% of patients taking TPV vs 2.2% of patients taking CPI (p<0.05). AST 3.5% vs 1.2% (p<0.05). Patients receiving TPV were more likely to experience grade 3-4 elevations of cholesterol (>400 mg/dL): 2.5% receiving TPV vs 0.5% receiving CPI (p<0.05). The same for triglycerides: 20.1% of patients receiving TPV vs 10.2% of patients receiving CPI had triglycerides >750 mg/dL (p<0.0001). AE related discontinuations: TOV/r 6.9%, CPI 4/7%.
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