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Day 2 at Glasgow: Tipranavir (RESIST-2); ATV/r v LPV/r 96 wks
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Reported by Jules Levin
Seventh International Congress on Drug Therapy in HIV Infection
November 14-18, Glasgow, UK
Margaret Johnson is reporting 96 week results from study BMS 045, which compares once daily Reyataz/ritonavir (300/100) to Kaletra (lopinavir/ritonavir twice daily in 358 treatment-experienced patients. As well, RESIST-2 results on tipranavir are presented here & reported in this article. Study 045 is a prospective, randomized open-label trial in patients who failed >=2 ART regimens containing 1 or more PI, NNRTI, and NRTI. Patients were originally randomized to 1 of 3 regimens: ATV/r, ATV/SQV, or kaletra. The ATV/SQV arm did not perform well. Previous to this report at Glasgow week 24 & 48 results were reported and can be found on the NATAP website & in NATAP's soon to be released newsletter. All patients also received tenofovir (TDF) and 1 NRTI selected based on genotype. The principle analysis was at weeks 24 & 48. This report will be abbreviated & more details will be reported later in the week. The results of this study were used by the FDA in granting approval for ATV/RTV 300/100 for treatment-experienced patients.
The recommended dose for ddI was reduced to 250mg or less, depending on weight, due to the interaction with TDF.
In the primary analysis, similarity (noninferiority) of efficacy between either of the ATV regimens and the LPV regimen was based on an upper 97.5% confidence interval (CI) for the TAD estimate of <0.5 log copies/ml. The ITT analysis was Treatment Response Without Prior failure (TRWPF). TRWPF used a response definition of a minimum of two sequential HIV RNA measurements
RESULTS
BASELINE CHARACTERISTICS. 22% men. 60% white, 23% latino, 16% black. 28% had AIDS. 16% had HCV. HIV RNA median 4.45 log. 24% >100,000 copies/ml. Median CD4 count- 300. 30% with <200 CD4.
DISCONTINUATIONS: 44% in ATV/r, 35% in LPV/r. 7% due to AE in ATV/r, 6% in LPV/r. Treatment failure: 27% ATV/r, 20% LPV/r. 56% of ATV/r & 53% of LPv/r remained on study at week 96.
PRIOR ARV use, median: equal for both arms: 2.5 PIs, 5.2 NRTIs, 1.4 NNRTIs. 36% previously had a PI & 58% a NNRTI. Phenotypic susceptibility at screening: 73% to ATV, 72% to LPV/r. Presence of 4 mutations at baseline: PI- 33% in ATV/r, 38% in LPV/r; NRTI- 42% ATV/r, 46% LPV/r.
MEAN CHANGE IN HIV RNA (baseline to week 96; n=64 in each arm): -2.29 log ATV/r; -2.08 LPV/r. (TAD CI: ATV/r-LPV/r 0.14 (-0.13, 0.41)
VIROLOGIC RESPONSE <400 copies/ml, ITT*:
43% LPV/r, 42% ATV/r. (Difference Estimate: ATV/r-LPV/r: -1.4 [95% CI: -13.9, 11.0])
VIRAL RESPONSE <50 copies/ml, ITT*:
33% LPV/r, 30% ATV/r. (difference Estimate: ATV/r-LPV/r: -3.3 [95% CI: -15.0, 8.4])
*Treatment response Without Prior failure
LIPIDS
total cholesterol (from baseline): -7% for ATV/r vs +9% for LPV/r (p<.0001)
LDL-C (fasting): -11% ATV/r vs +1% LPv/r.
HDL-C: -5% ATV/r vs +7% for LPV/r (p<0.05)
Triglycerides: -2% ATV/r vs +30% LPV/r (fasting) p<.0001
USE OF LIPID LOWERING AGENTS (on study)
Prior use: 6% ATV/r; 8% LPV/r
Week 48: 8% ATV/r; 19% LPV/r p<0.05
Week 96: 9% ATV/r, 20% LPV/r p<0.05
USE OF ANTIDIARRHEAL AGENTS (on study)
Prior use: 0 ATV/r, 5% LPV/r
Week 48: 6% ATV/r vs 24% LPV/r p<0.001
Week 96: 6% ATV/r, 25% LPV/r p<0.05
Authors reported no difference observed in efficacy for the ddI/TDF combination compared to TDF & other NRTI combinations (post hoc).
RESIST-2
This is the 24-week analysis of the phase III study comparing tipranavir (500/200 rtv) to the comparator PI arm. 38% of patients in Comparator arm (CPI/r) took LPV/r, 2.6% IDV, 20% SQV, 39% APV. 11.5% used T20. Ongoing PI selected in 30%. Phenotypic baseline PI resistance: 11-100 fold resistant to all PIS & 1.4 fold to TPV. Patients were highly treatment-experienced: median prior 12 ARVs (6 NRTIs, 1 NNRTI, and 4 PIs). Patients were highly resistant to all PIs at baseline except to TPV.
ITT NC=F PROPORTION WITH TREATMENT RESPONSE
1 or more log VL reduction
41% TPV/r (n=271)
14.9% CPI (n=268)
HIV RNA CHANGE FROM BASELINE ITT LOCF
CPI: -0.22 log
TPV/R: -1.6 log at week 4, -0.72 log at week 24
PROPORTION WITH <400
33.6% TPV/r vs 13.1% CPI
<50 copies/ml
TPV/r: 22.5%
CPI: 8.6%
IMPACT OF T20
<400 copies/ml: 38.5% TPV/r; 13% CPI/r
<50 copies/ml: 23.1% vs 4.3%
CD4 + 31 in TPV/r vs +1 in CPI/r.
AE related to disct: 6.9% TPV/r; 4.7% CPI/r.
Grade 3 or 4 ALT or AST elevations more common in patients on TPV/r: ALT 5.2% vs 2.2% p<0.05; AST: 3.5% TPV/r vs 1.2% CPI/r p<0.05.; mostly asymptomatic: only 6 patients (1.4%) disct.. Grade 3-4 lipid elevations more comm
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