Comparison of lipid profile with nevirapine versus atazanavir/ritonavir, both combined with tenofovir DF and emtricitabine (TDF/FTC), in treatment-naïve HIV-1 infected patients: ARTEN Study Week 48 results
Reported by Jules Levin
11th International Workshop on Adverse Drug Reactions and Co-morbidities in HIV, 26-28 October 2009, Philadelphia, USA
D Podzamczer1, V Soriano2, J Andrade-Villanueva3, B Clotet4, S Taylor5, J Rockstroh6, P Domingo7, P Reiss8, HJ Gellermann9, V Cairns9, L de Rossi9
1Hospital Universitario de Bellvitge, Barcelona, Spain; 2Hospital Carlos III, Madrid, Spain; 3Antiguo Hospital Civil de Guadalajara, Guadalajara, Mexico; 4Hospital Universitari Germans Trias i Pujol and irsiCaixa Foundation, Barcelona, Spain; 5Birmingham Heartlands Hospital,
Birmingham, UK; 6University of Bonn, Bonn, Germany; 7Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 8Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and 9Boehringer Ingelheim, Ingelheim, Germany
This study was supported by Boehringer Ingelheim GmbH
NVP containing regimens were associated with markedly greater increases in HDL-c and ApoA1 plasma levels, and an increase in LDL levels
Unlike with ATZ/r, no increase in TG concentrations and a reduction in TC:HDL-c ratio over 48 weeks was observed with NVP
While demonstrating non-inferiority between NVP and ATZ/r (both combined
with fixed dose TDF/FTC) with regard to treatment response at Week 48, ARTEN
data suggest a more favourable lipid profile for nevirapine
Objectives: Antiretroviral (ARV) therapy-associated dyslipidaemia contributes to
increased risk of cardiovascular disease in HIV-positive patients. Nevirapine (NVP) and atazanavir/ritonavir (ATZ/r) are effective ARVs with favourable lipid profiles. Along with efficacy and safety, the ARTEN study compares the metabolic profiles of these ARVs, both combined with tenofovir DF and emtricitabine.
Methods: ARTEN is an international, randomised, open-label study comparing ATZ/r 300mg/100mg once-daily vs. NVP 200mg twice-daily or 400mg once-daily, each combined with fixed-dose tenofovir DF 300mg/emtricitabine 200mg once-daily. Treatment-naïve men and women with CD4 counts <400 and <250 cells/mm3, respectively, were eligible. Changes in fasting plasma levels of total cholesterol (TC) and fractions (HDL-c and LDL-c), TC:HDL-c ratio, apolipoprotein A1 and B, and total triglyceride (TG) levels were determined from baseline to Wk-48. Lipid data obtained after initiation of lipid-lowering therapy were excluded. ITT (LOCF, last available observation carried forward) analyses were performed on all randomized patients receiving at least one dose of study medication. NVP arms were combined for greater power.
Results: 569 patients were randomised and treated; by Wk-48, 43/188 (22.9%) NVP once-daily patients, 56/188 (29.8%) NVP twice-daily patients and 18/193 (9.3%) ATZ/r patients had discontinued treatment or had missing discountinuation information. Results for lipid parameters are presented in Table 1.
TC = total cholesterol; TG = triglycerides; HDL-c = high density lipoprotein cholesterol; LDL-c = low density lipoprotein cholesterol; ApoA1 = apolipoprotein A1; ApoB = apolipoprotein B
*ANCOVA difference between treatments (least squares mean absolute changes from baseline to Wk-48 [LOCF]), controlling for baseline VL and CD4 categories (hence slightly different numbers for the difference NVP-ATZ/r)
Conclusion/Discussion: Compared with ATZ/r, NVP-containing regimens were associated with markedly greater increases in HDL-c and ApoA1 concentrations, a greater increase in LDL, less increase in TG concentrations and a reduction in TC:HDL-c ratio over 48 weeks. Overall, data suggest a more favourable lipid profile for NVP than ATZ/r, when combined with tenofovir DF and emtricitabine.
Some ARV therapies have been associated with a higher risk of myocardial infarction.1
Furthermore, some ARV therapies can adversely affect lipid and glucose metabolism.2
Increased levels of apolipoprotein A1 and HDL-c have been associated with a
decreased risk of coronary heart disease in the general population.3
The ARTEN Phase IIIb trial compared the virologic efficacy and safety of nevirapine (NVP) and ritonavir-boosted atazanavir (ATZ/r) both in combination with tenofovir DF and emtricitabine (TDF/FTC).4
In the ARTEN study, the combined NVP arms showed a similar efficacy to ATZ/r
(Figure 1) with a more favourable lipid profile after 48 weeks.4
This subanalysis presents the results for lipid parameters from the ARTEN study.
ARTEN is an open-label, randomised, international, non-inferiority clinical trial comparing the efficacy and safety of NVP versus ATZ/r in a total of 569 ARV-naïve patients with HIV-1-infection. It is the first prospective clinical trial to apply the guideline-recommended CD4+ cell count thresholds, of <250 cells/mm3 in women and <400 cells/mm3 in men, to the initiation of NVP.5-8 The ARTEN study included an arm with patients treated with NVP once-daily dosing, although NVP is not indicated for once-daily dosing and the efficacy and safety of NVP once-daily have not yet been established.
Along with efficacy and overall safety, the ARTEN study specifically compares the metabolic profiles of NVP and ATZ/r, both combined with TDF/FTC. Changes in fasting plasma levels of TC and lipoprotein fractions (HDL-c and LDL-c), TC:HDL-c ratio, apolipoprotein A1 and B, and TG levels over a 48 week period are reported here.
Key inclusion criteria:
· HIV-1-infected patients aged ≥18 years
· Adequate renal function (creatinine clearance ≥50 mL/min)
· Not previously treated with ARVs for >7 days
· CD4+ cell counts <400 cells/mm3 or <250 cells/mm3 for male and female patients,
Key exclusion criteria:
· Hepatic cirrhosis stage Child-Pugh B or C
· DAIDS grade >2 laboratory parameters (DAIDS grade >3 triglycerides)
· Active hepatitis B or C, defined as HBsAg-positive or HCV-RNA positive with AST or ALT >2.5x ULN (DAIDS grade 1)
Patients were randomised (1:1:1) to receive i) NVP 200 mg BID, ii) NVP 400 mg QD or iii) ATZ 300 mg QD plus RTV 100 mg QD (ATZ/r), in combination with fixed-dose FTC 200 mg QD/TDF 300 mg QD. Randomisation was stratified according to HIV-1 RNA (>100,000 copies/mL or ≤100,000 copies/mL) and CD4+ cell count (≥50 cells/mm3 or <50 cells/mm3) at screening. During the first 14 days of the study both NVP BID and NVP QD dose groups started out with a lead-in dose of NVP 200mg QD according to the product label.
Primary endpoint at Week 48:
· Treatment response (TR) was defined as the proportion of patients with HIV-1
RNA <50 copies/mL measured at two consecutive visits prior to Week 48 and
without subsequent rebound or change of ARV therapy prior to or at Week 48.
This was based on recommendations from the EACS guidelines at the time of
the trial design
Secondary endpoints at Week 48:
· Sensitivity analysis: A time to loss of virologic response (TLOVR) algorithm was applied, which defined TR as the proportion of patients with HIV-RNA <50
copies/mL at two consecutive visits up to Week 48 and without subsequent
rebound or change of ARV therapy prior to or at Week 48
· Changes in lipid parameters
- Changes in fasting plasma levels of TC and lipoprotein fractions (HDL-c and
LDL-c), TC:HDL-c ratio, apolipoprotein A1 and B, and TG levels
Safety endpoints included the incidence of adverse events (AEs), serious adverse events (SAEs) and discontinuations due to AEs, DAIDS grade ≥2 laboratory abnormalities and changes from baseline in laboratory tests over time.
The statistical analysis of efficacy and safety was performed on all randomised patients receiving at least one dose of study medication. For the primary efficacy analysis, an intention-to-treat, non-completers considered failures (ITT-NCF) analysis was performed.
The primary analysis was the test of non-inferiority of the combined NVP arms
compared to ATZ/r. The non-inferiority test was performed by calculating the twosided 95% confidence interval (CI) for the difference in the proportions of responders between the combined NVP groups and ATZ/r. Non-inferiority of combined NVP was established if -12% was excluded from the CI.
Analyses of fasting lipids over time excluded values obtained after the initiation of
lipid lowering therapy. Mean changes in fasting lipids from baseline were compared between treatment regimens with 95% CIs from baseline to Week 48 using last observation carried forward (LOCF).
Demographic data and HIV baseline characteristics
A total of 576 patients were enrolled and randomised to treatment; 569 received study medication (70.8% in Western Europe, 21.4% in Latin America and 7.7% in Eastern Europe).
Primary efficacy and safety results
Primary efficacy and safety data have been presented previously4 and are summarized below. At Week 48, a comparable proportion of patients achieved and maintained a TR (primary endpoint, ITT-NCF analysis) in the combined NVP group compared with the ATZ/r group (Table 2).
Non-inferiority of combined NVP vs. ATZ/r was established in the primary analysis (lower limit of the CI was above the pre-defined -12% non-inferiority margin at Week 48), and was confirmed by the sensitivity analysis (TLOVR algorithm) (Table 2).
Overall, AE rates were similar between groups (85.9% among combined NVP patients and 86.5% among ATZ/r patients). However, despite similar AE rates, the incidence of AE-related treatment discontinuations up to database lock for the analysis (beyond Week 48) was lower with ATZ/r than with combined NVP (3.6% vs. 13.6%). Rash was reported in 16.0% of combined NVP and 12.4% of ATZ/r patients, but more combined NVP patients were discontinued due to rash compared with ATZ/r (5.1% vs. 0%)
Most NVP-associated rashes developed during the lead-in phase. No Grade 4 rashes were observed. No cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, or deaths due to liver or skin toxicity occurred.
Changes in lipid parameters
Changes in total cholesterol and triglycerides
At baseline, TC and TG levels were comparable between the combined NVP and the ATZ/r treatment groups. NVP treated patients showed a numerically greater increase from baseline in TC and no increase in TG levels unlike with ATZ/r treated patients.
The mean increase in TC at Week 48 (LOCF) was 24.3 mg/dL in the combined NVP group and 19.9 mg/dL in the ATZ/r group (ANCOVA p-value: 0.055) (Figure 3). The mean increase in TG at Week 48 (LOCF) was -0.2 mg/dL in the combined NVP group and 27.2 mg/dL in the ATZ/r group (ANCOVA p-value: 0.0001) (Figure 3).
Changes in HDL-c, LDL-c and TC:HDL-c ratio
Baseline HDL-c and LDL-c levels were comparable between the combined NVP and ATZ/r treatment groups. The mean changes in HDL-c and LDL-c levels from baseline to Week 48 were statistically different between the combined NVP and the ATZ/r groups (Figure 4A), with NVP achieving greater mean changes of 9.7 mg/dL and 15.0 mg/dL, respectively, compared with ATZ/r which achieved mean changes of 3.9 mg/dL and 10.6 mg/dL.
Significant differences were observed between the combined NVP and ATZ/r treatment groups with regard to the effects on TC-HDL-c ratio. NVP reduced the TC-HDL-c ratio from baseline to Week 48, whereas ATZ/r increased the ratio (Figure 4B). The mean decrease with combined NVP was -0.24 and the mean increase with ATZ/r was 0.13 (ANCOVA p-value: 0.0001 for the difference between NVP and ATZ/r).
Absolute lipid values at Week 48
The mean TC, TG, HDL-c and LDL-c levels at baseline and Week 48 for the two groups in relation to the NCEP guidelines9 are presented in Figure 5.
Changes in ApoA1 and ApoB
Baseline ApoA1 levels were comparable between treatment groups with a mean of 1.15 g/L in both the combined NVP group and the ATZ/r group. After 48 weeks (LOCF), the respective mean values were 1.33 g/L for NVP and 1.23 g/L for ATZ/r. There was a significantly greater increase from baseline in mean ApoA1 observed in combined NVP patients than in ATZ/r patients (Figure 6). At Week 48 (LOCF), the mean increase in the combined NVP arm was 0.18 g/L and 0.08 g/L in the ATZ/r arm (ANCOVA p-value: <0.0001). These results are in accordance with the NILE study.10
Baseline ApoB levels were comparable between treatment groups, with a mean of 0.76 g/L in both the combined NVP group and the ATZ/r group. Changes in mean ApoB levels from baseline to Week 48 were minor; mean increases of only 0.02 g/dL to Week 48 (LOCF) were observed in both groups (Figure 6).
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