Introduction.
Since the late nineties, studies on HIV-infected individuals have reported a wide spectrum of metabolic alterations associated with Highly Active Antiretroviral therapy (HAART) including changes in glucose homeostasis and fat redistribution [1]–[3]. As the lifespan of HIV-infected individuals have been prolonged, due to a decline in HIV-associated morbidity and mortality on account of HAART [4]–[5], such metabolic imbalances could affect the long-tem prognosis due to progression of insulin resistance to diabetes mellitus (DM) and subsequent risk of end-organ disease.

In addition to the well known risk factors for DM [6], immunodeficiency, lipodystrophy, socioeconomic class, concurrent hepatitis C infection (HCV), and drug abuse have been described as possible risk factors [3], [7]–[13]. Since the US Food and Drug Administration in 1997 issued a warning on the diabetogenic effects of protease inhibitors (PIs), risk of glucose alterations in HIV-infected individuals have been largely attributed to this drug class [14]–[18]. Additionally, nucleotide reverse transcriptase inhibitors (NRTIs) have been proposed to accelerate the pathogenetic mechanisms of DM development, but the data are limited [7], [9]–[11], [18]–[22]. As insulin resistance and impaired glucose tolerance induced by HAART might act as a precursor of DM, risk of DM might be increased in the HAART era. Several studies have addressed the risk of DM in the HIV-infected population [7], [9]–[11], [18]–[19], [21]–[24], but the results are conflicting and the majority of the studies are hampered by mixed ethnicity and lack of a comparison cohort from the general population.

We aimed to conduct a nationwide, population-based cohort study in the period 1 January 1996 to 1 January 2010 to investigate the risk of DM in HIV-infected individuals compared to that of the general population. To evaluate the impact of certain risk factors we further examined the influence of age, body mass index (BMI), lipoatrophy, HAART and specific antiretroviral drugs on risk of DM in HIV-infected individuals.

Abstract.
Objective
In a nationwide, population-based cohort study we assessed the risk of diabetes mellitus (DM) in HIV-infected individuals compared with the general population, and evaluated the impact of risk factors for DM in HIV-infected individuals.

Methods
We identified 4,984 Danish-born HIV-infected individuals from the Danish HIV Cohort Study and a Danish born population-based age- and gender-matched comparison cohort of 19,936 individuals (study period: 1996–2009). Data on DM was obtained from the Danish National Hospital Registry and the Danish National Prescription Registry. Incidence rate ratios (IRR) and impact of risk factors including exposure to Highly Active Antiretroviral Therapy (HAART) and antiretroviral drugs were estimated by Poisson regression analyses.

Results
In the period 1996–1999 risk of DM was higher in HIV-infected individuals compared to the comparison cohort (adjusted IRR: 2.83; 95%CI: 1.57–5.09), both before (adjusted IRR: 2.40; 95%CI: 1.03–5.62) and after HAART initiation (adjusted IRR: 3.24; 95% CI: 1.42–7.39). In the period 1999–2010 the risk of DM in HIV-infected individuals did not differ from that of the comparison cohort (adjusted IRR: 0.90; 95% CI: 0.72–1.13), although the risk was decreased before HAART-initiation (adjusted IRR: 0.45; 95%CI: 0.21–0.96). Increasing age, BMI and the presence of lipoatrophy increased the risk of DM, as did exposure to indinavir, saquinavir, stavudine and didanosine.

Conclusion
Native HIV–infected individuals do not have an increased risk of developing DM compared to a native background population after year 1998. Some antiretroviral drugs, not used in modern antiretroviral treatment, seem to increase the risk of DM.