Metabolic Profiles and Body Composition Changes in Treatment-Naïve HIV-Infected Patients Treated with Raltegravir 400 mg bid-based vs. Efavirenz 600 mg qhs-based Combination Therapy: 96-Week Follow-Up
Reported by Jules Levin
CROI 201 Feb 16-20
E. DeJesus1, C. Cohen2, J. Lennox3, A. Lazzarin4, D. Berger5, B. Jin6, H. Teppler6, B-Y. Nguyen6, R. Leavitt6, P. Sklar6 for the STARTMRK (P021) Investigators
1Orlando Immunology Center, Orlando, FL, USA; 2Community Research Initiative of New England, Boston, MA, USA; 3Emory University, Atlanta, GA, USA; 4University Vita-Salute San Raffaele, Milan, Italy; 5Northstar Medical Center, University of Illinois at Chicago, Chicago, IL, USA; 6Merck Research Labs, North Wales, PA, USA
· At Week 96, both the RAL and EFV regimens demonstrated modest effects on serum lipids and glucose.
- The mean changes from baseline in total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglyceride concentrations were significantly smaller for RAL than for EFV recipients.
- The change in the total cholesterol/HDL-cholesterol ratio was not significantly different between the treatment groups.
· At week 96, DEXA showed small gains in body fat in both treatment groups.
· Longer-term experience with RAL suggests a favorable metabolic profile associated with minimal changes in body composition in treatment-naïve patients.
Background: Raltegravir (RAL) is a 1st in class integrase strand-transfer inhibitor. Metabolic parameters, including DEXA, were compared between RAL- and efavirenz (EFV)-based regimens after 96 weeks (wk) of treatment.
Methods: Patients (Pts) were randomized in a double-blind study of RAL vs EFV, each with TDF/FTC (n=563). Groups were compared for metabolic parameters, including fasting lipid and glucose abnormalities according to DAIDS criteria, NCEP goals, and lipoatrophy (defined as at least a 20% decrease from baseline in appendicular fat) with follow-up through 96 wk. DEXA scans were obtained on a subset of pts (n=86) at baseline and Wk 48, and on a subset of pts (n=75) at both baseline and Wk 96.
Results: At Wk 96, RAL had less impact on fasting lipids, including total, low-density lipoprotein (LDL-C) and high-density lipoprotein (HDL-C) cholesterol levels, triglycerides (trig) as well as glucose than EFV; the impact on the total:HDL-C ratio was similar (Table 1). Fat changes by DEXA appear to be similar on average at Wk 96 (Table 2).
N = Number of patients in the treatment group.
Mean % change from baseline are based on the measurements of the patients who were measured at both baseline and the time point assessed.
The DEXA re-scan (for the baseline visit) values were taken as the baselines for 7 patients and clinically deemed acceptable, when the original baseline scan readings were not available.
Note: RAL and EFV were administered with TRUVADATM
· While the majority of patients in both groups experienced modest fat gain, 3/37 pts on RAL and 2/38 pts on EFV had at least 20% appendicular fat loss (lipoatrophy).
Conclusion: Through Wk 96, RAL demonstrated minimal effects on serum lipids and glucose levels. DEXA showed minimal gains in body fat, with no patterns of fat loss in both treatment groups. Longer-term experience with RAL suggests a favorable metabolic profile in treatment-naive patients.
Background and Objectives
· Metabolic abnormalities have been reported with many antiretroviral therapies, characterized by lipid abnormalities, glucose intolerance, and undesirable patterns of fat gain and fat loss (lipoatrophy).
· RAL is a novel HIV-1 integrase inhibitor with potent efficacy, and a favorable safety profile.1,2
- Minimal changes in lipid, glucose levels, and body composition in treatment-naïve patients have been reported through Week 48.3
- The current presentation provides follow-up to Week 96.
1 Steigbigel RT, 96-week results from Benchmrk 1&2, phase III studies of raltegravir (ral) in patients (pts) failing antiretroviral therapy (ART) with triple-class resistant HIV, 16th Annual Conference on Retroviruses and Opportunistic Infections, February, 2009.
2 Lennox JL, et al, Raltegravir demonstrates durable efficacy through 96 weeks: results from STARTMRK, a phase III study of raltegravir (RAL)-based vs efavirenz (EFV)-based combination therapy in treatment-naïve HIV-infected patients, ICAAC, [Abstract# H924B], San Francisco, CA, September 11, 2009.
3 DeJesus E, et al, Metabolic profiles and body composition changes in treatment-naïve HIV-infected patients (pts) treated with raltegravir (ral) 400 mg bid -based vs. efavirenz (efv) 600 mg qhs -based combination therapy: 48-week data, [Abstract# H1571], ICAAC, San Francisco, CA, September 11, 2009.
Overall Efficacy and Safety Results1
· RAL provides potent and statistically non-inferior viral suppression compared to EFV
· RAL has a numerically greater immunological effect than EFV, measured by an increase in CD4 cell counts
· RAL is generally better tolerated than EFV
- significantly fewer overall and drug-related clinical adverse events
- significantly lower percentages of patients with CNS side-effects
1 Lennox JL, et al, Raltegravir demonstrates durable efficacy through 96 weeks: results from STARTMRK, a phase III study of raltegravir (RAL)-based vs efavirenz (EFV)-based combination therapy in treatment-naïve HIV-infected patients, ICAAC, [Abstract# H924B], San Francisco, CA, September 11, 2009.
Overall Study Design
· Double-blind, randomized (1:1), non-inferiority study (n=563 Patients)
· RAL 400 mg bid vs EFV 600 mg qhs both in combination with
tenofovir/emtricitabine (TDF/FTC as Fixed Dose Coformulation)
· Key inclusion criteria
- no prior ART
- HIV RNA level >5000 copies/mL
- viral susceptibility to EFV, TDF, and FTC
- Efficacy: Proportion with HIV RNA levels <50 copies/mL, change in CD4 cell counts
- Safety/tolerability: adverse experiences; central nervous system (CNS) events; lipid changes from baseline
Metabolic Evaluation and DEXA Sub-Study Design
· We evaluated whether treatment was associated with metabolic abnormalities during extended follow-up through 96 weeks
· Treatment groups in the parent study were compared for metabolic parameters:
- Fasting lipid and glucose abnormalities according to DAIDS criteria
- NCEP lipid goals
- Investigator-reported lipodystrophy AE terms
· DEXA scans were obtained on a subset of 111 patients at baseline
- Patients at US sites were eligible.
· Only sites with access to the necessary equipment were included.
- Follow-up scans were performed at Week 48 and/or Week 96.
· Fat changes over time were plotted as in: Moyle G, et al, Body Composition changes in treatment-naïve patients treated with boosted PIs plus TDF/FTC: results from the CASTLE study through 96 weeks. Presented at 12th European AIDS Conference/EACS, 11-14 November 2009, Cologne, Germany, Abstract #LBPS11/6. - Lipoatrophy was defined as ≥ 20% loss of baseline appendicular fat.
Statistical Approaches to Missing Data for the Metabolic Analyses
· Lipid Profile
- Last Observation Carried Forward approach
· If patients initiated or increased dosage of lipid-lowering therapy, last available lipid values prior to the use of lipid-lowering therapy were used in the analysis
· Body Composition (DEXA) and Glucose
- Complete data set approach
· Patients needed to have values at both baseline and Week 48 (or Week 96) to be included in the analysis
There were 111 patients with DEXA scans at baseline: 86 patients were evaluable at Week 48 and 75 patients were evaluable Week 96, including 68 patients evaluable at both time points. One patient in the substudy was not scanned at baseline.
· Median baseline BMI (kg/m2) was higher in the RAL group than the EFV group overall (25.8 vs. 24.7).
· There were fewer females in the RAL group than in EFV group in the DEXA substudy [4 (7%) vs. 9 (16%)].
Mean Change from Baseline in Metabolic Parameters at Week 96
· The change from baseline in the T CHOL:HDL-C ratio was -0.18 for the RAL group and -0.04 for EFV group (p=0.192).
Note: Lipoatrophy is defined as more than a 20% decrease from baseline appendicular fat at Week 96.