 |
|
|
| |
Tipranavir-New Protease Inhibitor- for Resistance: 24-week results
|
| |
| |
Reported by Jules Levin
--630 patients with extensive treatment-experience resistance to protease inhibitors were randomized to tipranavir or another boosted PI regimen. Here are the 24-week results, presented at ICAAC Oct 29 2004 in a late breaker by Charles Hicks (UNC).
--Patients were highly treatment experienced: median of 12 prior antiretroviral HIV medications: 6 NRTIs, 2 NNRTIs, 4 protease inhibitors; patients had an average of 15 baseline protease mutations.
--41.5% of patients taking tipranavir vs 22.3% taking other PI regimens had at least 1 log reduction in viral load (p<0.0001) (Intent-To-Treat: non-completer=failure analysis, most stringent).
--34.7% of patients taking tipranavir vs 16.5% taking other PI regimens had <400 copies/ml (ITT: non-completer=failure analysis)
--If also taking Fuzeon, 47% taking TPV/r vs 21.9% taking other PI regimens had <400 cp/ml
--25.1% of patients taking tipranavir vs 10% of patients taking other PI regimens had <50 copies/ml. If also taking Fuzeon: 32.8% taking TPV/r vs 14.3% taking other PI regimens had <50 cl/ml
--viral load reduction at week 24: -0.88 for patients taking TPV/r vs -0.28 for patients taking other PI regimens. About 36% of patients in the study were taking Fuzeon. Hicks commented that TPV/r treatment response was improved with use of other active ARV drugs in the optimized background regimen.
--to qualify for the study patients needed 1 or more primary PI mutation at codons: 30N, 46I/L, 48V, 82A/F/L/T, 84V, or 90M
and
2 or less mutations at codons: 33, 82, 84, or 90. This is because TPV/r response is muted when more of these mutations are present.
Tipranavir is a new protease inhibitor for patients with extensive resistance to protease inhibitors. Tipranavir is expected to receive FDA approval around the end of the 3rd quarter 2005. If a person needs immediate access to tipranavir, an Expanded Access Program is expected to begin very soon & a patient can gain access through their doctor to the EAP. As well, Roche is making Fuzeon available to take along with tipranavir in this study if a patient needs availability. This way a patient can start with two new drugs and this should help achieve the best viral load reductions that can be durable. We have long awaited the study results presented at ICAAC (Oct, 2004). RESIST 1 and RESIST 2 are the large phase III studies conducted by Boerhinger Ingleheim examining the antiviral activity and safety of tipranavir. The 24-week results of RESIST 1, which is the US based study, was reported at ICAAC, and RESIST results will be reported at the European HIV Conference in Glasgow Nov 12, 2004. Tipranavir is dosed at 500 mg twice daily along with 200 mg of ritonavir also twice daily to boost tipranavir levels. RESIST study participants were randomized to tipranavir or other boosted PI regimens, and all participants also received nukes.
Other new HIV drugs that are expected to be effective against resistance in development include TMC-114 & TMC-125 (PI & NNRTI), Reverset (NRTI), and several entry inhibitors. But these drugs are not expected to be available for at least 1 year except through clinical trials.
Here is key study results. Participants in RESIST-1 had baseline phenotypic resistance testing and had extensive resistance to other protease inhibitors: 77.8-fold resistance to lopinavir (Kaletra), 39-fold to indib=navir (Crixivan), 27-fold to saquinavir (Fortovase, Invirase), and 12-fold resistant to amprenavir. 61% of the study participants who were not randomized to receive tipranavir/r were given Kaletra, 4.4% were given indinavir, 20.6% wre given saquinavir, and 14% were given amprenavir, all boosted by ritonavir. 36% of the participants also received Fuzeon. Of note, some participants were taking Fuzeon before the study started so they may have already had Fuzeon resistance. While some patients started Fuzeon along with tipranavir for the first time in this study. It is very important to start a new regimen with at least two potent drugs that the patient is very sensitive to. So, it is likely that the patients who started fresh with both Fuzeon & tipranavir/r had the best viral load reductions and will sustain the best durability of those reductions.
This was a highly treatment-experienced patient population having had prior treatment experience with a median of 6 NRTIs, 2 NNRTIs, and 4 PIs, for a total of 12 median prior antiretrovirals. Patients had on average 15 protease inhibitor mutations before starting the study.
Baseline resistance testing was performed, before treatment regimens were selected. Patients and their doctors could access an HIV resistance expert panel to pre-select, but apparently most doctors & patients did not seek this advise because tolerability was important in which comparator PI was selected.
BASELINE CHARACTERISTICS. Patients in the two arms were well matched in terms of demographics. Average age: 44 yrs; 90% male; 77% white, 22% black; 7.7-11% had HCV; median CD4 count was 123 & viral load was 4.83 log (about 70,000 copies/ml).
The study authors reported 48 patients discontinued through 24 weeks in the TPV arm and 139 in the other PI arm. 13 withdrew from the TPV/r arm due to virologic failure & 109 in the other PI arm discontinued due to virologic failure. 25 in the TPV/r arm & 9 in the other PI arm withdrew due to adverse events, but investigators said this was because more patients withdrew in the other PI arm due to virologic failure & more patients remained on the TPV/r arm.
Failures in the other PI arm after 8 weeks could receive TPV/r in a rollover study; failure was defined as viral load drop of <=0.5 log or viral load >100,000 copies/ml; rebound to <1 log decrease in viral load.
TREATMENT RESPONSE was defined as the proportion of patients with a 1 log or greater reduction in viral load at week 24. This was the primary endpoint of the study: 41.5% taking TPV/r vs 22.3% taking other PI regimen achieved this response (p<0.0001).
HIV RNA MEDIAN CHANGE FROM BASELINE (ITT: LOCF)
Patients taking TPV/r had a median -1.5 log reduction in viral load at week 4 & at week 8. Median viral load reduction was -0.88 at week 24 for patients taking TPV/r vs -.28 for patients taking other PI regimen (p<0.001). Investigators said this was because these patients on average did not have a potent enough regimen to sustain the initial 1.5 log reduction in viral load. This is why it's crucial to take at least two fresh new drugs when starting a new regimen, and why starting with Fuzeon and TPV/r together should help in achieving & sustaining maximal viral load reduction.
PROPORTION WITH UNDETECTABLE VIRAL LOAD at WEEK 24 (ITT: non-completer=failure)
Proportion of patients with <400 copies/ml was 34.7% taking TPV/r vs 16.5% taking other PI regimen. Patients also taking Fuzeon: 47.1% taking TPV/r vs 21.9% taking other PI regimen. This suggests that patients who started a fresh regimen, taking Fuzeon for the first time along with TPV/r had a better response than 47% <400 c/ml. This data will be presented at CROI. A more detailed analysis of patients taking Fuzeon is expected at CROI. Proportion of patients with <50 copies/ml: 25.1% taking TPV/r vs 10% taking other PI arm. For patients also taking Fuzeon: 32.8% taking TPV/r vs 14.3% taking other PI regimen.
CD4 increases were on average 36 for patients taking TPV/r vs 6 for patients taking other PI regimens (p<0.001) (ITT:LOCF). Remember baseline CD4 count was on average low 123.
GRADE 3 or 4 ADVERSE EVENTS
Cumulative reported grade 3-4 events occurred in >=1% of patients at week 24.
| TPV/r | Other PIs | | Diarrhea | 2.9% | 2.6% | | Nausea | 2.3% | 0.3% | | Fatigue | 1.0% | 1.0% | | Pyrexia | 1.3% | 0.6% | | Dehydration | 1.3% | 0.3% | | Headache | 1.0% | 0.6% | | TOTAL AEs | 22.8% | 18.1% |
GRADE 3-4 LAB ABNORMALITIES
Elevations in liver enzymes and lipids (CHOL, TG) appear to occur more often in the TPV/r arm. 19/22 TPV/r patients with grade 3-4 ALT/AST were asymptomartic & continued treatment/ 64/66 patients with grade 3-4 triglycerides (TG) continued treatment.
| TPV/r | Other PIs | p-value | | Leukopenia (<1000 cells/mm3) | 5.5% | 7.5% | ns | | ALT | 6.9% | 1.3% | <0.001 | | AST | 4.6% | 1.6% | 0.06 | | Amylase | 6.9% | 7.2% | ns | | Lipase | 2.9% | 1.6% | ns | | Cholesterol | 4.2% | 0 | <0.01 | | Triglycerides | 21.7% | 12.5% | <0.01 | | Increased glucose | 2.0% | 1.6% | ns |
|
| |
|
|
|
|
|
