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Efficacy and Safety of Atazanavir-based Therapy in Antiretroviral Naive HIV-1 Infected Subjects, Both with and without Ritonavir: 48-week Results from AI424-089
Niel Malan*1, E Krantz2, N David3, K Kastango4, D Frederick4, M Matthew4, S Schnittman4, J Hammond4, and the -089 Study Group
1Triple M Res, Port Elizabeth, South Africa; 2Quinta-Res, Bloemfontein, South Africa; 3Cape Town, South Africa; and 4Bristol-Myers Squibb Pharma Res Inst, Wallingford, CT, US
Background: Atazanavir (ATV) is a potent, generally well
tolerated once-daily protease inhibitor that has been extensively studied without
ritonavir (RTV) in ART-naïve, and when boosted with RTV, in
treatment-experienced patients; however, data on the use of ATV with RTV (ATV/r)
in ARV-naïve subjects are limited.
Methods: Study AI424-089 is a 96-week, randomized,
open-label, prospective study comparing the efficacy and safety of ATV/r 300 mg/100 mg with
ATV 400 mg, both in combination with lamivudine (3TC) and extended-release stavudine
(d4T), all given once daily, in ART-naïve subjects. The primary endpoint was the
proportion of subjects with HIV RNA<400 copies/mL through week 48; planned secondary
assessments included proportion with HIV RNA <50 copies/mL, CD4 count change,
and safety parameters.
Results: We randomized 200 subjects, of whom we
treated 199. At baseline, the mean CD4 count was 235 cells/mm3, the
mean HIV RNA 4.95 log10 copies/mL, the mean total cholesterol 161
mg/dL, and the mean triglyceride level 145 mg/dL. Discontinuations prior to
week 48 were few: ATV/r, 12%; ATV, 10%. The
rate of drug-related adverse events of at least moderate intensity was comparable
between arms. Adverse events-related discontinuations occurred more commonly in
the ATV/r arm (8%) than the ATV arm (1%); these were primarily
protocol-mandated for persistent hyperbilirubinemia. Jaundice and scleral
icterus (all grades) were more common in the ATV/r arm (22%; 23%) than the ATV
arm (7%; 13%). Mean increase in total cholesterol was 15% for the ATV/r arm vs
6% for the ATV arm (p <0.01); mean
increase in triglycerides was 26% for ATV/r vs –3% for ATV (p <0.01); a shift of ³1
NCEP triglyceride category occurred in 16% for ATV/r vs 11% for ATV.
|
Week 48
Efficacy Results
|
ATV/r
|
ATV 400
|
Difference Estimate (95% CI)
(ATV/r - ATV400)
|
|
HIV RNA
(Intent to Treat, TLOVR)
|
n = 95
|
n = 105
|
|
|
% with <400 copies/mL
|
86
|
85
|
1.5 (–8.2, 11.1)
|
|
% with <50 copies/mL
|
75
|
70
|
5.0 (–7.0,
17.0)
|
|
|
|
HIV RNA
(On Treatment)
|
n = 84
|
n = 94
|
|
|
% with <400 copies/mL
|
93
|
93
|
0.2 (–7.4,
7.8)
|
|
% with <50 copies/mL
|
87
|
76
|
11.2 (–0.2,
22.6)
|
|
|
|
Mean CD4 from Baseline (cells/mm3)
|
189
|
224
|
–21.1 (–48.9, 6.6)*
|
*Time-averaged difference through Week 48
Conclusions: In this study in ART-naïve HIV+subjects,
ATV, with or without RTV, demonstrated a high rate of virologic response
through 48 weeks. Both arms were generally safe and well tolerated, although subjects
on ATV/r had a higher rate of hyperbilirubinemia. These results support
additional studies using ATV/r in ART-naïve subjects.
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