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A Pilot Study of Abacavir/Lamivudine (ABC/3TC) and Raltegravir (RAL) in Antiretroviral Naive HIV-1 Infected Subjects
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Reported by Jules Levin
EACS Nov 13 2009 Cologne Germany
B Young1, T Vanig2, E DeJesus3, T Hawkins4, M St. Clair5, L Yau5,
B Ha5 and the SHIELD Study Team
1Rose Medical Center/Division of General Internal Medicine, University of Colorado, Denver, CO and Health Connections International, Amsterdam; 2Spectrum Medical Group, Phoenix, AZ; 3Orlando Immunology Center, Orlando, FL; 4Southwest CARE Center, Santa Fe, NM; 5GlaxoSmithKline, RTP, NC
ABSTRACT
Background - RAL is a HIV-1 integrase strand-transfer inhibitor with potent in vitro activity that has not been evaluated with ABC/3TC in antiretroviral naïve HIV-1 infected subjects. The objective of this study was to evaluate the efficacy and safety of ABC/3TC+RAL as initial therapy.
Methods - This is a 96-week, open-label, pilot, prospective, multicenter study evaluating ABC/3TC (600 mg/300 mg once-daily) + RAL (400 mg twice daily) in HLA-B*5701 negative subjects with entry viral load (VL) >1,000 c/mL. Virologic failure (VF) was defined as failure to achieve VL <400 c/mL by Wk 24 or confirmed rebound ≥ 400 c/mL or confirmed 1 log10 c/mL increase above nadir. The planned Wk 24 interim analysis is reported.
Results - 35 subjects were enrolled. Baseline (BL) characteristics were: median HIV-RNA 4.80 log10 c/mL (34% ≥ 100,000 c/mL), median CD4 count 301 cells/mm3 (20% <200 cells/mm3). Median CD4 cell change from BL was 193 cells/mm3. Virologic response is given below:
No subject experienced VF through Wk 24. One subject had uncontrolled diabetes at BL. At Wk 24, median change from BL (interquartile range) were 22 mg/dL (8-36) for cholesterol, 9 mg/dL (-4-22) for LDL-C, 4 mg/dL (-1-8) for
HDL-C, and 20 mg/dL (-14-76) for triglycerides; change from BL (95% confidence intervals) were -15% (-39% to 17%) for hs-CRP and -19% (-43% to 15%) for interleukin-6.
Conclusions - In this pilot study, RAL+ABC/3TC achieved rapid virologic suppression and exhibited potent antiretroviral activity through Wk 24. Wk 24
cardiovascular inflammatory biomarker levels tested were not significantly different from BL.
INTRODUCTION
While the availability of new treatment options for HIV addresses many of the unmet needs for clinical care, each prospective combination of antiretroviral drugs should be evaluated for potency, tolerability, and treatment-emergent
resistance patterns.
The combination of abacavir sulfate 600 mg + lamivudine 300 mg (ABC/3TC [EPZICOM® ], GlaxoSmithKline, RTP, NC) and the integrase inhibitor raltegravir (RAL [Isentress® ], Merck & Co., Inc., Whitehouse Station, NJ) has not been studied previously.
METHODS
The SHIELD study (COL111429) is an ongoing 96-week, open-label, prospective, multicenter trial evaluating ABC/3TC (600 mg/300 mg once daily) +
RAL (400 mg twice daily) in antiretroviral-naïve HLA-B*5701-negative adults with screening HIV-1 RNA >1,000 c/mL.
Subject were excluded if they had an active or acute CDC Clinical Category C event at screening, were HBSAg+, or if their screening HIV-1 genotype indicated the presence of any of the following mutations: K65R, L74V, and Y115F or a
combination of two or more thymidine analog mutations (M41L, D67N, K70R, K219Q or E) that included changes at either L210 or T215, associated with ABC and 3TC resistance, and mutations Q148H/R/K and N155H associated with RAL
resistance. There were no restrictions on baseline CD4 cell count.
Virologic failure is defined as having either confirmed virologic non-response (HIV-1 RNA >400 c/mL at week 24 [W24]) or confirmed virologic rebound (HIV-1 RNA ≥ 400 c/mL after an initial response of HIV-1 RNA <400 c/mL or >1 log10 c/mL increase above nadir). In the case of clinically suspected hypersensitivity to ABC, subjects are permitted to substitute ABC/3TC with lamivudine 150 mg and zidovudine 300 mg (ZDV/3TC [COMBIVIR® ], GlaxoSmithKline, RTP, NC) twice
daily and will not be discontinued from the study.
The primary efficacy endpoint of this study is the percentage of subjects with HIV-1 RNA <50 c/mL at W48. The primary safety endpoint is the percentage
of subjects with treatment-related grade 3 or 4 adverse events (AEs) and laboratory abnormalities. This poster presents the results of a planned 24-
week interim analysis.
RESULTS
Thirty-five subjects with a mean age of 39 years enrolled in the study. Most were white males, but 26% of subjects self-identified as Hispanic or Latino. At baseline, 34% had HIV-1 RNA ≥ 100,000 c/mL, and 20% had CD4 cell counts <200 cells/mm3.
Subject Accountability: Thirty four (34) of 35 subjects completed W24. The status of 1 subject was unknown at the time of the data cut, but the subject was later determined to be lost-to-follow-up.
Safety Results: Through W24, 11% (4/35) of subjects experienced treatment-related grade 2 to 4 AEs; only fatigue (n=2) occurred in >1 subject. No subject experienced treatment-related serious AEs. Six (6) patients experienced grade 3/4 laboratory abnormalities, including increased cholesterol, triglycerides, creatine kinase, glucose, AST, lipase, and inorganic phosphorus. One subject had uncontrolled diabetes at baseline. There were no suspected hypersensitivity reactions to abacavir.
EFFICACY RESULTS
For this interim analysis at W24, 94% (33/35) of subjects had HIV-1 RNA <50 c/mL and 97% (34/35) had HIV-1 RNA <400 c/mL using an ITT, missing-equals-failure analysis. No subject met the criteria for virologic failure.
At W24, the median increase from baseline in CD4 cell count was 193 cells/mm3.
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