Background:  Insulin resistance (IR) has been of increased concern since the introduction of effective ART, but the associated factors remain ill-defined. We determine the relationship of the type and duration of ART exposure with IR in a nationally representative sample of HIV⁺ and at-risk HIV^– women.

Methods: Prospective cohort study between October 2000 and March 2007 of 1614 HIV⁺ and 604 HIV^– participants from the Women's Interagency HIV Study. The homeostasis model assessment (HOMA) defined as [fasting insulin (µIU/mL) x fasting glucose (FG) (mg/dL)]/405 estimated IR at 11,019 semiannual visits. The first visit with both FG and insulin data available was considered the index visit.

Results:  HIV⁺ women had higher median HOMA (2.19 vs 1.83, p <0.001) at index. After adjustment, HIV⁺ women had larger median HOMA than HIV^– women: 1.20 (95%CI 1.11 to 1.30) times larger for those reporting protease inhibitor (PI) -containing HAART since the prior visit; 1.10 (95%CI 1.01 to 1.20) times larger for those reporting non-PI-containing HAART since the prior visit. Those reporting mono/combination ART and no ART since the prior visit had larger HOMA than HIV^– women, but the association did not reach statistical significance:  1.05 (95%CI 0.93 to 1.19 and 1.05 (95%CI 0.96 to 1.15), respectively. Other factors associated with larger HOMA in multivariable analysis included body mass index (per 5 unit increase:  1.18; 95%CI 1.16 to 1.20), hepatitis C virus (HCV) seropositivity (1.17; 95%CI 1.09 to 1.24), Hispanic ethnicity compared to African American (1.13; 95%CI 1.06 to 1.19), menopause (1.11; 95%CI 1.02 to 1.21), family history of diabetes mellitus (1.05; 95%CI 1.00 to 1.11), and CD4 count (per 100 cell increase) (1.01; 95%CI 1.00 to 1.02). Among HIV⁺ women, cumulative exposure to nucleoside reverse transcriptase inhibitors (NRTI) of >0 to 3 years or >3 years was associated with median HOMA 1.06 (95%CI 0.98 to 1.16) and 1.13 (95%CI 1.02 to 1.25) times larger, respectively, than the HOMA without any cumulative NRTI exposure. Cumulative exposure to stavudine of >0 to 1 year or >1 year was associated with HOMA 1.07 (95%CI 0.98 to 1.16) and 1.15 (95%CI 1.05 to 1.27) times larger, respectively, than the HOMA without any cumulative stavudine use.

Conclusions: Longer cumulative exposure to NRTI; in particular stavudine was associated with greater insulin resistance in HIV⁺ women. The role of insulin resistance and cardiovascular disease in HIV⁺ individuals remains a paramount clinical concern.