Insulin sensitivity in multiple pathways is differently affected during zidovudine/lamivudine-containing compared with NRTI-sparing combination antiretroviral therapy

J Acquir Immune Defic Syndr. 2010 Feb;53(2):186-93. doi: 10.1097/QAI.0b013e3181c190f4.


Objective: The extent and manner by which HIV nucleoside reverse transcriptase inhibitors contribute to insulin resistance is unclear. We evaluated the effect of zidovudine/lamivudine (ZDV/3TC) on glucose metabolism.

Methods: combination antiretroviral therapy-naive men were randomized to lopinavir/ritonavir (LPV/r, 400/100 mg twice a day) + ZDV/3TC or LPV/r (533/133 mg twice a day) + nevirapine (NVP). Computerized tomography, dual-energy X-ray absorptiometry scans, and hyperinsulinemic euglycemic clamps using stable isotopes were performed before and after 3, 12, and 24 months of combination antiretroviral therapy.

Results: Insulin-stimulated peripheral glucose disposal decreased by 25% after 3 months in patients on zidovudine/lamivudine/lopinavir/ritonavir (ZDV/3TC/LPV/r) (P < 0.001) and this decreased rate persisted thereafter, followed by a transient decrease in insulin-mediated inhibition of lipolysis. In the nevirapine/lopinavir/ritonavir (NVP/LPV/r) group, hepatic insulin sensitivity had improved compared with baseline after 24 months. After the initial 3 months, limb fat decreased in the ZDV/3TC/LPV/r arm up to 24 months [-849 +/- 345 g (P = 0.017)], and visceral adipose tissue increased over 2 years [+36.2 +/- 13.3 cm2 (P = 0.009)]. In the NVP/LPV/r group, a generalized increase in fat mass was observed.

Conclusions: Treatment with ZDV/3TC/LPV/r versus NVP/LPV/r differentially affects glucose and lipid metabolism. The ZDV/3TC/LPV/r regimen induced peripheral insulin resistance, a transient increase in basal lipolysis and a transient decrease in insulin-mediated inhibition of lipolysis, whereas hepatic insulin sensitivity improved with the NVP/LPV/r regimen.

Trial registration: NCT00122226.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-HIV Agents / pharmacology
  • Blood Glucose / drug effects*
  • Body Composition / drug effects
  • Drug Therapy, Combination
  • HIV Infections / drug therapy*
  • Humans
  • Insulin Resistance*
  • Intra-Abdominal Fat / drug effects
  • Lamivudine / pharmacology*
  • Lipids / blood
  • Lipolysis / drug effects
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Middle Aged
  • Zidovudine / pharmacology*


  • Anti-HIV Agents
  • Blood Glucose
  • Lipids
  • Lamivudine
  • Zidovudine

Associated data