susceptibility: L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D or I84V.
As-treated analyses were also conducted to assess virologic outcome by the number of primary protease inhibitor substitutions present at baseline. Response rates were reduced if five or more protease inhibitor-associated substitutions were present at baseline and subjects did not receive concomitant new enfuvirtide with APTIVUS/ritonavir. See Table 9.
Table 9 Controlled Clinical Trials 1182.12 and 1182.48: Proportion of Responders (confirmed ≥1 log10 decrease at Week 48) by Number of Baseline Primary Protease Inhibitor (PI) Resistance Associated Substitutions
Number of Baseline
Primary PI Mutationsa |
APTIVUS/ritonavir
N=578 |
Comparator PI/ritonavir
N=610 |
|
No New Enfuvirtideb |
+ New Enfuvirtidec |
No New Enfuvirtideb |
+ New Enfuvirtidec |
|
a Primary PI mutations include any amino acid substitution at positions 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 and 90 |
|
b No new enfuvirtide is defined as recycled or continued use of enfuvirtide or no use of enfuvirtide |
|
c New enfuvirtide is defined as initiation of enfuvirtide for the first time |
|
Overall |
38%
(180/470) |
69%
(75/108) |
18%
(92/524) |
26%
(22/86) |
|
1 - 2 |
62%
(24/39) |
60%
(3/5) |
33%
(14/43) |
0%
(0/1) |
|
3 - 4 |
48%
(96/202) |
71%
(27/38) |
23%
(45/193) |
38%
(13/34) |
|
5+ |
26%
(60/229) |
69%
(45/65) |
11%
(33/288) |
18%
(9/51) |
The median change from baseline in plasma HIV-1 RNA at weeks 2, 4, 8, 16, 24 and 48 was eva luated by the number of baseline primary protease inhibitor resistance associated substitutions (1-4 or ≥5) in subjects who received APTIVUS/ritonavir with or without new enfuvirtide. The following observations were made:
-
Approximately 1.5 log10 decrease in HIV-1 RNA at early time points (Week 2) regardless of the number of baseline primary protease inhibitor resistance associated substitutions (1-4 or 5+).
-
Subjects with 5 or more primary protease inhibitor resistance associated substitutions in their HIV-1 at baseline who received APTIVUS/ritonavir without new enfuvirtide (n=303) began to lose their antiviral response after Week 4.
-
Early HIV-1 RNA decreases (1.5-2 log10) were sustained through Week 48 in subjects with 5 or more primary protease inhibitor resistance associated substitutions at baseline who received new enfuvirtide with APTIVUS/ritonavir (n=74).
Baseline Phenotype and Virologic Outcome Analyses
APTIVUS/ritonavir response rates were also assessed by baseline tipranavir phenotype. Relationships between baseline phenotypic susceptibility to tipranavir, mutations at protease amino acid codons 33, 82, 84 and 90, tipranavir resistance-associated mutations, and response to APTIVUS/ritonavir therapy at Week-48 are summarized in Tables 10 and 11. These baseline phenotype grou
