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908/r: 48 WEEK RESULTS in PI-EXPERIENCED (CONTEXT STUDY)
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--ANALYSIS OF VIROLOGIC RESPONSE BASED UPON BASELINE GENOTYPE & BPHENOTYPE
Reported by Jules Levin
BRIEF SUMMARY
Patients receiving 908/r twice daily: 58% had <400 copies/ml; 46% < 50 copies/ml
Patients receiving Kaletra (LPV/r) twice daily: 61% had <400 copies/ml; 50% had <50 copies/ml (ITT RD=F), There were 27% virologic failures in each arm.
At week 48 viral load reduction was --908/r bid: -1.53 (0.94) log c/ml; and LPV/r bid: -1.76 (0.93) log c/ml. 908/r once daily did not perform well in this study in PI-experienced patients, so it is not recommended for use in PI-experienced, but it is approved to be used in PI-naïve patients. Below, in this article, you'll find a Virology substudy which compares the two regimens, 908/r & LPV/r, regarding virologic responses in the presence of PI resistance.
315 patients who had failed 1-2 PIs with current treatment failure (HIV RNA >1000 c/ml at screening) were randomized to receive 2 N(t)RTIs with:
--908/r 1400/200 mg QD
--908/r 700/100 mg bid
--LPV/r 400/100 mg bid
Subjects did not have to be taking aPI at study entry, 2/3 were receiving aPI at entry. Baseline RT genotype was used to optimize NRTI backbone. Baseline protease genotype was not used for entry/randomization criteria.
BASELINE DEMOGRAPHICS | 908/r QD | 908/r bid | LPV/r bid | | n=105 | n-107 | n=103 | | Females | 16% | 13% | 17% | | Median age | 42 | 40 | 41 | | Wh, Bl, Hisp (%) | 73/19/7 | 70/21/8 | 57/32/11 | | Hep B, C | 7%/15% | 4%/15% | 5%/17% | | CDC Class C | 34% | 32% | 34% | | Med HIV RNA | 4.19 log | 4.13 log | 4.13 log | | Med CD4 count | 250 | 292 | 234 |
PRIOR ART EXPOSURE
This data suggests that patients receiving 908/r had more prior ART experience than patients receiving LPV/r.
| 908/r QD | 908/r bid | LPV/r | | -median duration of prior PI (wks) | 149 | 149 | 130 | | ->=2 prior PIs taken % of subjects | 57% | 49% | 40% | | -median duration prior NRTIs (wks) | 234 | 257 | 210 | | ->=3 prior NRTIs taken % of subjects | 70% | 79% | 64% | | -median duration prior NNRTIs (wks) | 87 | 84 | 78 | | ->=2 prior NNRTIs % of subjects | 11% | 14% | 8% |
BASELINE RESISTANCE
Although patients receiving 908/r appeared to have more ART experience, the following data does not necessarily suggest much difference in drug resistance between patientsreceiving 908/r and LPV/r.
Mean (median)
| 908/r QD | 908/r bid | LPV/r | | PRIMARY PI MUTATIONS | 1 (1) | 0.9 (1) | 1 (1) | | >3 primary PI mutations | 7% | 8% | 11% | | secondary PI mutations | 2.8 (3) | 2.8 (3) | 3 (3) | | phenotypic resistance to all PIs (>2.5) | 8% | 16% | 9% | | NRTI mutations | 2.3 (2) | 2.6 (3) | 2.4 (2) | | TAMS | 1.3 (0) | 1.7 (2) | 1.4(1) | | >3 TAMS | 28% | 38% | 24% | | M184V | 60% | 49% | 56% |
WEEK 48 RESULTS
Average Area Under the Curve (AUC) minus Baseline (AAUCMB) at Week 48:
Mean AAUCMB (std dev) at week 48 (observed):
908/r QD: -1.49 (0.91) log c/ml
908/r bid: -1.53 (0.94) log c/ml
LPV/r bid: -1.76 (0.93) log c/ml
PROPORTION OF SUBJECTS WITH PLASMA HIV RNA LEVELS <400 and <50 COPIES/ML
908/r QD is not recommended for PI-experienced patients
(HIV RNA <400 c/ml- 50%; HIV RNA <50 c/ml- 37%)
| 908/r bid | LPV/r | | n=107 | n=103 | | RESPONDER (ITT RD=F) | | | | -HIV RNA <400 c/ml | 58% | 61% | | -HIV RNA <50 c/ml | 46% | 50% | | VIROLOGIC FAILURES HIV RNA >400 c/ml | 27% | 27% |
SAFETY
Grade 2-4 drug related AEs were comparable between 908/r bid & LPV/r bid.
UPPER GI EVENTS
| nausea: | 908/r: 3% | LPV/r: 9% | | vomiting: | 908/r 3% | LPV/R: 5% |
No grade 3/4 total colesterol elevations were observed in either treatment group.
Grade 3/4 lipase elevations: 908/r bid- 5%, LPV/r: 12%
Grade 3/4 triglycerides elevations: 908/r bid- 11%, LPV/r- 6%
VIROLOGY OBJECTIVE
Identify statistically robust phenotypic and genotypic clinical cut-offs for 908/r.
Virologic response: <400 c/ml at week 48
Virology population:
--all subjects who received at least one dose of randomized PI
--subjects were excluded if the study drug was discontinued for reasons other than virologic failure (eg- adverse events).
--908/r bid n=92, LPV/r bid n=88
VIROLOGY ANALYSIS
Phenotypic Clinical Cut-off:
a statistically robust phenotypic cut-off could not be established due to the distribution of the baseline data.
Genotypic Based Analysis:
The most robust differentiation between virological response & failure was associated with the presence at baseline of-
--3 primary PRO mutations (p=0.009)
--6 or more primary/secondary PRO mutations (p=0.007)
--4 or more Marcellin et al mutations (p<0.001)
(L10F/I/V, K20M/R, E35D, R41K, L63P, V82A/F/T/S, I84V).
RESPONSE AT WEEK 48 BY PRESENCE OF PRIMARY PI-mutations at BASELINE
Most patients had >1 PI resistance-associated mutation at baseline, and not all patients had a fully active NRTI backbone.
In a press release, GSK said these were the most common PI associated mutations seen at baseline among the 210 patients included in the study:
L90M in 63 patients (30 percent)
M46I/L in 48 patients (23 percent)
D30N in 45 patients (21 percent)
| Baseline Mutation | 908/r bid | LPV/r bid | | D30N | 21/25 95% | 17/18 (94%) | | M46I/L | 11/22 50% | 12/24 50% | | L90M | 16/31 52% | 17/28 (61%) | | V82A/F/T/S | 2/9 22% | 6/17 35% | | I84V | 1/6 17% | 2/5 40% |
It is unknown what effect therapy with LEXIVA will have on the activity of subsequently administered protease inhibitors. Clinical relevance of resistance data is currently being evaluated.
M46I/L at BASELINE & RECEIVED 908/r BID: RESPONDERS vs NON-RESPONDERS
<400 c/ml (responders), n=11
>400 c/ml, n=11 (nonresponders)
MEAN NUMBERS
RESPONDERS had 2 primary PRO mutations, while non-responders had 3.
RESPONDERS had 5 primary & secondary PRO mutations, while non-responders had 7.
RESPONDERS had 4 total number of RT mutations, while non-responders had 5.
RESPONDERS had 1 PI-fold resistance, while non-responders had 5 foldPI resistance.
RESPONDERS had 2 number of susceptible concomitant NRTIs, while non-responders had 1.
M46I/L at BASELINE: RESPONSE IN THE PRESENCE/ABSENCE OF BASELINE RESISTANCE
| Genotype | Phenotype | Combined | ODDS RATIO 95% CI | | Evidence of Resistance | Yes | No | Yes | No | Yes | No | | | 908/r | 20% | 59% | 25% | 80% | 23% | 89% | 0.038 | | (>2.5-FC) | 1/5 | 10/17 | 3/12 | 8/10 | 3/13 | 8/9 | (0.0008, 0.55) | | LPV/r | 22% | 67% | 29% | 100% | 33% | 100% | | | (>2.5 FC) | 2/9 | 10/15 | 5/17 | 7/7 | 6/18 | 6/6 | - | | LPV/r | 22% | 67% | 14% | 65% | 18% | 77% | 0.067 | | (>10 FC) | 2/9 | 10/15 | 1/7 | 11/17 | 2/11 | 10/13 | (0.005,0.65) |
The likelihood of a successful response in patients with baseline M46I/L iseduced in the presence of baseline protease mutations.
Genotypic Resistance 908/r: I54L/M, V32I, I50V, I84V. LPV/r: Abbott algorithm.
L90M at BASELINE & RECEIVED 908/r BID RESPONDERS vs NON-RESPONDERS
RESPONDERS had 1.5 number of primary PRO mutations, while non-responders had 2.
RESPONDERS had 5 primary & secondary PRO mutations, while non-responders had 6.
RESPONDERS had 4 total number of NRTI mutations, while non-responders had 5.
RESPONDERS had 1 fold PI resistance, while non-responders had 5 fold PI resistance.
RESPONDERS had 1 number of susceptible concomitant NRTIs, while non-responders had 1.
L90M at BASELINE: RESPONSE IN THE PRESENCE/ABSENCE OF BASELINE RESISTANCE
| Genotype | Phenotype | Combined | ODDS RATIO 95% CI | | Evidence of Resistance | Yes | No | Yes | No | Yes | No | | | 908/r | 22% | 64% | 17% | 72% | 20% | 81% | 0.056 | | (>2.5-FC) | 2/9 | 14/22 | 2/12 | 13/18 | 3/15 | 13/16 | (0.007, 0.43) | | LPV/r | 17% | 73% | 23% | 93% | 23% | 93% | 0.021 | | (>2.5 FC) | 1/6 | 16/22 | 3/13 | 14/15 | 3/13 | 14/15 | (0.0005, 0.29) | | LPV/r | 17% | 72% | 20% | 70% | 14% | 76% | 0.052 | | (>10 FC) | 1/6 | 18/22 | 1/5 | 18/23 | 1/7 | 16/21 | (0.001, 0.65) |
The likelihood of a successful response in patients with baseline L90M isreduced in the presence of baseline proteaseresistance.
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