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Efficacy and Safety of Once-daily Atazanavir/Ritonavir Compared to Twice-daily Lopinavir/Ritonavir, Each in Combination with Tenofovir and Emtricitabinein ARV-naive HIV-1-infected Subjects: The CASTLE Study, 48-week Results
Jean-Michel Molina*1, J Andrade-Villanueva2, J Echevarria3, P Chetchotisakd4, J Corral5, N David6, M Mancini7, L Percival7, A Thiry7, and D McGrath7
1Hosp St Louis, Paris, France; 2Hosp Civil de Guadalajara, Mexico; 3Hosp Natl Cayetano Heredia, Lima, Peru; 4Khonkaen Univ, Thailand; 5Hosp Intl Gral de Agudos Oscar Alende, Buenos Aires, Argentina; 6Brooklyn Med Ctr, Western Cape, South Africa; and 7Bristol-Myers Squibb R&D, Wallingford, CT, US
Background: Atazamavor/ritonavir (ATV/r) is as
effective as lopinavir (LPV)/r with more favorable lipid and gastrointestinal profiles
in treatment-experienced HIV-infected patients. Comparative data in ARV-naive
patients are needed.
Methods: CASTLE is a randomized, open-label,
multicenter, ongoing 96-week study to assess non-inferiority (10% margin) of
ATV/r 300 mg/100 mg once-daily vs LPV/r 400 mg/100 mg twice-daily, both in
combination with fixed-dose tenofovir (TDF) 300 mg/emtricitabine (FTC) 200 mg once-daily,
in treatment-naοve patients. The primary endpoint was the proportion of
patients with HIV RNA<50 copies/mL at week 48; planned secondary assessments
included percent with HIV RNA <400 copies/mL, CD4 cell count change, and
safety.
Results: Of the 883 patients we randomized, 878 were
treated. Baseline demographics and characteristics were well balanced. Median CD4 205 cells/mm3; median plasma HIV RNA 4.98 log10
copies/mL. At week 48, mean CD4 increases from baseline for ATV/r
and LPV/r were 203 and 219 cells/mm3, respectively. Fewer patients
on ATV/r (2%) than LPV/r (8%) initiated lipid-lowering therapy. The proportion
of patients with a total cholesterol (TC):HDL ratio >5 at week 48 was 12%
and 20% on ATV/r and LPV/r, respectively. Patients on ATV/r had a lower
incidence of grade 2-4 treatment-related diarrhea (2% vs 11%) and nausea (4% vs
8%) than LPV/r. Grade 3-4 alanine aminotransferase/aspartate aminotransferase (ALT/AST)
elevations were low (≤2%) on both arms. Discontinuations prior to week 48
were: ATV/r, 9%; LPV/r, 13%. Adverse event-related discontinuations were 2% and
3% on ATV/r and LPV/r, respectively; 3 patients (<1%) discontinued ATV/r due
to jaundice/hyperbilirubinemia.
Conclusions: In treatment-naive patients, ATV/r demonstrated
similar efficacy, a lower incidence of gastrointestinal-related adverse events,
and a significantly better lipid profile (TC, triglycerides, non-HDL) compared
to LPV/r. In combination with TDF and FTC, both ATV/r and LPV/r were well
tolerated with few discontinuations through 48 weeks.
|
|
ATV/r
|
LPV/r
|
Difference Estimate (95%CI)
(ATV/r LPV/r)
|
|
CVRa
|
n = 440
|
n = 443
|
|
|
% <50 copies/mL
|
78
|
76
|
1.7 (3.8 to 7.1)
|
|
% <400 copies/mL
|
86
|
82
|
3.3 (1.5
to 8.1)
|
|
CVRa, Baseline CD4 < 50
cells/mm3
|
n = 58
|
n = 48
|
|
|
% <50 copies/mL
|
78
|
63
|
|
|
Fasting Lipid Mean % D from baseline at 48 weeksb
|
n = 421
|
n = 415
|
|
|
Total-C (TC)
|
12
|
24
|
9.5 (11.8
to 7.0)c
|
|
LDL
|
12
|
15
|
2.9 (7.1
to 1.5)
|
|
HDL
|
27
|
32
|
3.8 (7.8
to 0.3)
|
|
Non-HDL
|
7
|
21
|
11.6 (14.5
to 8.7)c
|
|
TG
|
13
|
51
|
25.2 (29.8
to 20.2)c
|
|
a Confirmed Virologic Response (ITT),
Non-Completers = Failure
b Last Observation Carried Forward
c p < 0.0001
|
|
