9th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV


19-21 July 2007, Sydney, Australia

ZIDOVUDINE/LAMIVUDINE PERSISTENTLY CONTRIBUTES TO PERIPHERAL INSULIN RESISTANCE BY A BODY COMPOSITION-INDEPENDENT MECHANISM DEMONSTRATED BY REPEATED CLAMP STUDIES DURING 2 YEARS OF FIRST-LINE ART WITH ZIDOVUDINE/LAMIVUDINE/LOPINAVIR/RITONAVIR

Antiviral Therapy 2007; 12(Suppl. 2):L13 (abstract no. O-15)

MGA van Vonderen1, RME Blümer2, E Hassink3, J Sutinen4, MT Ackermans2, MA van Agtmael1, H Yki-Jarvinen4, SA Danner1, HP Sauerwein2 and P Reiss2,3 and the MEDICLAS study group
1VU University Medical Center, Amsterdam, the Netherlands; 2Academic Medical Center, Amsterdam, The Netherlands; 3IATEC, Amsterdam, The Netherlands; 4Helsinki University Central Hospital, Helsinki, Finland

OBJECTIVES: NRTI are thought to contribute to insulin resistance by induction of lipoatrophy. Recently, however, stavudine was shown to reduce peripheral glucose disposal without changes in fat distribution within 4 weeks in healthy volunteers. We prospectively evaluated the role of zidovudine/lamivudine in glucose metabolism and body composition in HIV-infected patients initiating ART in a randomized trial.

METHODS: ART-naïve men were randomized to lopinavir/ritonavir (400/100 mg two times daily) + zidovudine/lamivudine or lopinavir/ritonavir (533/133 mg two times daily) + nevirapine. CT, DEXA and hyperinsulinaemic euglycaemic clamps (aimed at plasma insulin level 200 pmol/l) using stable isotopes were performed before and after 3, 12 and 24 months of ART. A mixed model repeated measures ITT analysis correcting for baseline differences was performed.

RESULTS: Baseline age was 42 ±9 years, BMI 23.3 ±3.1 kg/m2, CD4 count 201 ±90 cells/ml, HIV-1 RNA 5 ±0.5 log10 c/ml (comparable between arms). Lopinavir plasma exposure was not significantly different between both arms.

CONCLUSIONS: The persistent decrease in insulin-mediated glucose uptake observed only on zidovudine/lamivudine/ lopinavir/ritonavir, starting prior to measurable limb fat loss and visceral fat accumulation, suggests that zidovudine/ lamivudine, independent of any GLUT-4 inhibition by lopinavir/ritonavir, contributes to peripheral insulin resistance by a mechanism which seems independent of changes in fat distribution. The observed adiponectin increases in both arms are remarkable given the reduced levels reported in patients with clinical lipoatrophy, and may suggest a compensatory response early on after initiating ART for the first time.

Table 1. (Abstract O-15)
  Zidovudine/lamivudine/lopinavir/r   Nevirapine/lopinavir/r
 
 
  Baseline
(n=11)		 Mos 3
(n=11)		 Mos 12
(n=11)		 Mos 24
(n=10)		   Baseline
(n=9)		 Mos 3
(n=8)		 Mos 12
(n=9)		 Mos 24
(n=7)
Limb fat, kg 6.6 ±0.3 6.8 ±0.3 6.4 ±0.3 5.9 ±0.3*†   6.5 ±0.3 6.4 ±0.3 7.4 ±0.3 7.2 ±0.3
Total fat, kg 14.0 ±0.4 14.4 ±0.4† 14.6 ±0.4 14.6 ±0.5*   14.0 ±0.5 13.0 ±0.5 15.7 ±0.5 15.7 ±0.5‡
VAT, cm2 114 ±10.2 104 ±10.2 120v±10.6 150 ±10.7‡   115 ±11.4 97 ±11.8 124 ±11.4 123 ±12.4
SAT/TAT 0.54
±0.02		 0.56
±0.02		 0.55
±0.02		 0.50
±0.02		   0.53
±0.02		 0.53
±0.02		 0.53
±0.02		 0.56
±0.02
Rd glucose,
(mol/kg)/min		 23.1 ±1.6 17.5 ±1.6† 19.3 ±1.6 19.7 ±1.7†   22.5 ±1.7 23.6 ±1.9 21.0 ±1.7 25.3 ±1.9
Adiponectin, g/ml 6.5 ±0.5 7.0 ±0.5 8.1 ±0.5 8.6 ±0.6†‡   6.4 ±0.6 7.7 ±0.6 9.9 ±0.6 10.8 ±0.7‡
Data represent estimated means ±sem. Rd, rate of disposal; *P<0.05 between groups difference overall course 0–24 months; †P<0.05 between groups at visit; ‡P<0.05 within group 0–24 months. Mos, month.

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2007-07-24
O-15

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