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Cumulative exposure to nucleoside analogue reverse transcriptase inhibitors is associated with insulin resistance markers in the Multicenter AIDS Cohort Study

Brown, Todd Ta; Li, Xiuhongb; Cole, Stephen Rb; Kingsley, Lawrence Ac; Palella, Frank Jd; Riddler, Sharon Ac; Chmiel, Joan Sd; Visscher, Barbara Rc,e; Margolick, Joseph Bb; Dobs, Adrian Sa

Clinical Science

Objective: To estimate insulin resistance and its relationship to antiretroviral therapy (ART) in a cohort of HIV-infected persons with comparison to HIV-seronegative controls.

Design: Prospective cohort of 533 HIV-infected and 755 HIV-seronegative men in the Multicenter AIDS Cohort Study evaluated at 6-month intervals between 1999 and 2003.

Methods: Recent ART exposure was assessed by type of treatment in the preceding 6 months [i.e., no ART, monotherapy, combination ART, or highly active antiretroviral therapy (HAART) with and without a protease inhibitor (PI)]. Cumulative exposure was determined for the three major ART classes and for individual medications within each class. Two endpoints, a modified QUICKI index, 100 × 1/[log10(glucose) + log10(insulin)] and fasting hyperinsulinemia (insulin > 15 μU/ml), were assessed. All statistical models were adjusted for age, body mass index, race, nadir CD4 cell count, hepatitis C serostatus and family history of diabetes mellitus.

Results: Each of the HIV-infected groups had higher odds of hyperinsulinemia and lower mean QUICKI than the HIV-seronegative men. Each additional year of exposure to nucleoside analogue reverse transcriptase inhibitors (NRTI) was associated with increased odds of hyperinsulinemia [odds ratio (OR), 1.08; 95% confidence interval (CI), 1.02–1.13) and a lower QUICKI (−0.04; 95% CI, −0.07 to −0.01). Cumulative exposure to non-nucleoside analogue reverse transcriptase inhibitors or PI drugs was not associated with either insulin resistance marker. Of individual medications examined, stavudine was associated with the highest risk of hyperinsulinemia (OR, 1.2; 95% CI, 1.2–1.3).

Conclusions: Fasting surrogate markers suggest increased insulin resistance in HIV-infected men, which is related to cumulative NRTI exposure.

From the aJohns Hopkins University, School of Medicine

bBloomberg School of Public Health, Baltimore, Maryland

cUniversity of Pittsburgh, Pittsburgh, Pennsylvania

dFeinberg School of Medicine, Northwestern University, Chicago, Michigan

eUniversity of California at Los Angeles, Los Angeles, USA.

Received 4 January, 2005

Revised 26 April, 2005

Accepted 9 May, 2005

Correspondence to Dr T.T. Brown, 1830 East Monument St, Suite 333, Baltimore, MD 21287, USA. E-mail:

See Appendix for study members.

© 2005 Lippincott Williams & Wilkins, Inc.