Once-Daily Abacavir/Lamivudine (ABC/3TC) and Boosted Atazanavir (ATV/r): 48-Week Analysis from COL102060 (SHARE)
Reported by Jules Levin
4th IAS Conference, July 2007, Sydney, Australia
Elion R1, DeJesus E2, Sension M3, Berger D4, Towner W5, Richmond G6, Yau L7, Ha B7, COL102060 Study Team
1George Washington University, Washington, DC, USA, 2Orlando Immunology Center, Orlando, USA,
3Comprehensive Care Center, Fort Lauderdale, USA, 4Northstar Medical Center, Chicago, USA, 5Kaiser Permanente, Los Angeles, USA,
6Broward General Medical Center, Fort Lauderdale, USA, 7GlaxoSmithKline, RTP, USA
--At week 48, 77% of subjects achieved HIV-1 RNA <50 copies/mL by ITT: M=F analysis and 90% by ITT: observed analysis, and CD4+ cell count increased above baseline by a median of 188 cell/mm3.
--No new or unexpected adverse events or laboratory abnormalities were reported in this study: hyperbilirubinemia (5%), ocular icterus (5%), and grade 3-4 total bilirubin (46%) were frequently reported with ATV (in AI424-089 study: grade 3-4 total bilirubin [59%] and hyperbilirubinemia [13%]) [Mallan 2006]; suspected abacavir hypersensitivity reaction which has been well characterized, occurred at a frequency consistent with previously described reports (8%).
--Median fasting lipids at 48 weeks increased from baseline to week 48 and triglyceride levels exceeded the NCEP cut-off, similar to AI424-089 study [Mallan 2006]
--A slight increase in median LDL particle concentration from baseline to week 48 was observed.
--No major treatment-emergent PI-associated resistance mutations were selected in subjects who were virologic non-responders.
--Efficacy results are comparable to those reported from recent studies involving
other RTV-boosted PI regimens for initial therapy.
--Increases in fasting lipids were observed in the current study consistent with
observations reported in other studies involving RTV-boosted PI regimens.
--The study indicates that while ATV has been shown to have a modest impact on lipids compared with other PIs, the use of low-dose RTV appears to mitigate any lipid-related benefits of ATV.
--Median LDL particle concentrations at both baseline and at week 48 remained
within the same risk category (near or above optimal), as used in the Framingham Offspring study [Otvos 2002].
--ABC/3TC plus ATV/r regimen provides a high genetic barrier to resistance development.
--Combination ABC/3TC FDC QD + ATV/r QD is an effective and well tolerated regimen in ART-naive subjects, with a modest impact on fasting lipids.
--Further study is underway to determine whether simplifying therapy without RTV after virologic suppression will reverse observed hyperlipidemia.
--PIs have been linked with the development of metabolic complications such as
dyslipidemia, insulin resistance, glucose abnormalities, and lipodystrophy [Dube
--There is a need for PI-containing regimen that is potent and well tolerated without unfavorable lipid elevations while offering a high genetic barrier to resistance. ATV, the first PI approved for QD dosing, had been shown to have a more favorable lipid profile compared with other PIs in treatment-experienced subjects [Agarwal 2002; Badaro 2003]
--the time of study initiation , ATV 300 mg/RTV 100 mg plus ABC 600 mg/3TC 300 mg (Epzicom) once-daily (QD) had not been studied in treatment naive subjects.
--The objective of the present study was to evaluate the efficacy and safety of ABC/3TC + ATV/r QD in antiretroviral (ART)-naive subjects with plasma HIV-1 RNA >5,000 copies/mL.
Figure 1. Study Design: ATV/r + ABC/3TC
112 ART-naive patients received abacavir/3TC (600/300) once daily plus Reyataz/r (300/100) once daily. Substitutions were permitted for suspected abacavir HSR to AZT/3TC or to fosamprenavir. 86% (95) of patients completed 48 week study.
Table 1. Baseline Characteristics and Subject Disposition
91% men. 24% African-American, 54% Caucasian 17% Hispanic. Median HIV RNA 100,000 c/ml, 56% >100,000 c/ml. Median CD4 count 207, 16% <50 Cd4s, 31% 50-200, 53% >200 CD4s. 1% prematurely withdrew due to virologic failure, 3% due to adverse event*.
Figure 5. NMR Lipoprotein Particle Number Analysis
Nuclear magnetic resonance (NMR) directly quantifies lipoprotein subclass
particles, not the cholesterol inside.
NMR analysis is rapid, automated and reproducible, and requires no
physical separation of the particles.
LDL particle number as measured by NMR has consistently been shown to
be a strong, independent predictor of cardiovascular risk.
Histograms for low-density lipoprotein (LDL) cholesterol (Friedewald estimate) and nuclear magnetic resonance-measured LDL particle concentration from the Framingham Offspring Study (n=3,437).
Table 4. Virologic Outcome and Resistance Through 48 Weeks
Confirmed virologic non-responders (VNRs)*: 4/111 (4%).
Unconfirmed rebound to >/=400 c/ml+: 6/111 (5%)
VNRs with baseline and post-baseline genotypes: 8/10
Subjects with treatment-emergent mutations: 1/8
NRTI mutations: 0
PI-associated mutations (secondary M36I/M)**
1. Agarwala S, Russo R, Mummaneni V, et al. Steady-state pharmacokinetic (PK) interaction of atazanavir (ATV) with ritonavir (RTV) in healthy subjects. In: Abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA 2002. Abstract H-1716.
2. Otvos JD, Jeyarajah EJ, Cromwell WC. Measurement issues related to lipoprotein heterogeneity. Am J Cardiol 2002;90:22i-29i.
3. Grundy SM; National Cholesterol Education Program (NCEP)-The National Cholesterol Guidelines in 2001, Adult Treatment Panel (ATP) III. Approach to lipoprotein management in 2001 National Cholesterol Guidelines. Am J Cardiol. 2002;90:11i-21i.
4. Dube MP, Stein JH, Aberg JA, et al. Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medical
Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis. 2003;37:613-27.
5. Badaro R, DeJesus E, Lazzarin A, et al. Efficacy and safety of atazanavir (ATV) with ritonavir (RTV) or saquinavir (SQV) versus lopinavir/ritonavir (LPV/RTV) in combination with tenofovir (TFV) and one NRTI in patients who have experienced virologic failure to multiple HAART regimens: 16-week results from BMS AI424-045. In: 2nd IAS Conference on HIV Pathogenesis and
Treatment, Paris, France, 13-16 July 2003, Abstract 118.
6. Malan N, Krantz E, David N, et al. 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. In: Program and Abstracts of the 13th Conference on Retroviruses and Opportunistic Infections, February 5-8, 2006, Denver, Colorado, Abstract 107LB.
7. Jeyarajah EJ, Cromwell WC, Otvos JD. Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy. Clin Lab Med. 2006;26:847-70.