12th CROI Abstract #846

Session 147 Poster Abstracts
Clinical Studies of Hyperlipidemia, Fat Redistribution, and Glucose Metabolism
Thursday, 1:30 - 3:30 pm
Hall B

846

Lipid and Lipoprotein Changes during Short-term Protease Inhibitor and Efavirenz Exposure in HIV-seronegative Subjects
Susan Rosenkranz*¹, K Yarasheski², M Para³, R Reichman⁴, G Morse⁵, and the ACTG A5043 Team
¹Harvard Sch of Publ Hlth, Boston, MA, USA; ²Washington Univ, St Louis, MO, USA; ³Ohio State Univ, Columbus, USA; ⁴Univ of Rochester, NY, USA; and ⁵State Univ of New York at Buffalo, USA

Background: ART use is associated with altered lipid metabolism. It is unclear whether these alterations result from changes in fat distribution, immune or virologic status, or direct actions of ART. If the last, variation in ART areas under the curve (AUC), due to individual pharmacokinetics or drug interactions, could predict lipid levels, a hypothesis we tested in HIV-seronegative adults participating in the pharmacokinetic interaction study ACTG A5043.

Methods: Subjects took efavirenz (EFV) 600 mg once daily on days 1 to 21, amprenavir (APV) 600 mg twice daily on days 11 to 21, and were randomized to take a second protease inhibitors (PI) (saquinavir [SQV], nelfinavir [NFV], indinavir [IDV], ritonavir [RTV]), or none on days 15 to 21. Fasting serum cholesterol, triglylceride, LDL-C, and HDL-C were measured on days 0, 14, 21, and 42 (3 weeks after discontinuing all drugs). Nine, 10, 6, 8, and 7 subjects contributed C levels on the SQV, NFV, IDV, RTV, and control arms, respectively. Least-squares means for each day/arm were estimated from mixed-effects models without multiple comparisons adjustment.

Results: Baseline values and body mass index did not differ among arms. AMP+EFV significantly increased mean cholesterol, triglyceride LDL-C and HDL-C. Neither AMP nor EFV AUC predicted cholesterol, triglycerides, LDL-C, or HDL-C changes on day 14. Cholesterol, triglycerides, and LDL-C were still higher on day 21 on some arms. Three weeks after drug discontinuation, cholesterol, and LDL-C remained elevated over baseline. HDL-C increased from day 21 on the control, NFV and RTV arms. Body weight was unchanged during the study.

Least Squares Mean (mg/dL)

Day

Drugs

None

(95% CI)

AES

AEN

AEI

AER

None

(AE)

None

(AES)

None

(AEN)

None

(AEI)

None

(AER)

156

(147–164)

^a170

^b183

^b174

^b,c186

^b,c191

^b179

^d182

^d183

^d180

^d207

^d176

(79–109)

^a110

^b132

117

^b,c139

110

^b,c141

^e81

^d133

^e101

100

108

LDL

(83–98)

^a100

^b106

102

^b110

^b,c119

102

^d113

^d107

^d105

^d134

100

HDL

(42–49)

^a48

^b49

^d,e52

^d52

^d,e54

^a Day 14 differs from day 0 at p<0.05.

^b Day 21 differs from day 0 at p<0.05.

^c Day 21 differs from day 14 at p<0.05.

^d Day 42 differs from day 0 at p<0.05.

^e Day 42 differs from same arm on day 21 at p<0.05.

Conclusions: As previously reported, varying the second PI taken with APV+EFV yielded differing but similar AUC. Here, lipid changes were also similar across second-PI arms. Lipids did not correlate with APV and EFV AUC, but increased with the duration of APV and EPV exposure, and remained elevated in some subjects after drug discontinuation.

Keywords: lipids; boosted protease inhibitors; efavirenz