Among persons with HIV, initiating first combination antiretroviral therapy (cART) regimens with integrase strand transfer inhibitors (INSTIs) or protease inhibitors (PIs) vs non-nucleoside reverse transcriptase (NNRTI)-based therapy may lead to greater risk of diabetes mellitus (DM), according to data published in Clinical Infectious Diseases. Investigators suspect that increased DM risk is likely mediated through weight gain, which is associated with INSTI-based cART.

Investigators examined the impacts of initial cART regimen and weight on incident DM in the large North American HIV cohort (NA-ACCORD). They included cART-naïve adults at least 18 years of age who initiated INSTI-, PI-, or NNRTI-based regimens and had weight measured 12 (±6) months after treatment. Participants were followed and monitored until clinical DM, virologic failure, cART regimen switch, administrative close or death, or loss to follow-up.

Among the 22,884 eligible individuals, 47% started NNRTI-, 30% started PI-, and 23% started INSTI-based cART with median follow-up of 3.0, 2.3, and 1.6 years, respectively. Of these participants, 3% (n=722) developed diabetes mellitus. INSTI- vs NNRTI-initiators had an incident DM risk (hazard ratio (HR), 1.17; 95% CI, 0.92-1.48) similar to PI- vs NNRTI-initiators (HR, 1.27; 95% CI, 1.07-1.51). The effect was most pronounced for those starting with raltegravir- (HR, 1.42; 95% CI, 1.06-1.91) vs NNRTI-initiators. Investigators further found that the INSTI-DM association was attenuated (HR, 1.03; 95% CI, 0.71-1.49 vs NNRTIs) when accounting for 12-month weight.

Investigators noted that while they did use data from a large, multi-site, and broadly representative HIV cohort in the United States, the findings still may not be generalizable to HIV patients globally. There was no data regarding cART adherence or lipodystrophy measures that may be potential mediators. The intention-to-treat analytical framework made use of prescribed cART as a proxy for received cART. Missed diagnoses of DM may have occurred as the use of HbA1c may underestimate fasting blood glucose in people with HIV. Investigators may have missed participants P diagnosed using fasting blood glucose or oral glucose challenge testing and treated with diet and lifestyle modification rather than medication.

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This study did not consider exposure to non-HIV medications associated with weight gain (hormonal or psychotropic drugs, tobacco use, or physical activity), but inclusion may bias inferences as these factors were differentially distributed by initial cART class. Differences in sex-by-race categories were not examined, and the low percentage of women participants (14%) may not reflect the burden of treatment-associated DM among people with HIV worldwide. Investigators acknowledge that they “did not assess longitudinal changes in HbA1c or fasting glucose, and did not assess the development of pre-diabetes, the major risk factor for the development of DM.” However, they state that these may be seen as mediators on causal pathways that were not accounted for in this analysis.

Investigators conclude and advise that weight gain and metabolic health of patients initiating cART for HIV should be monitored. Data shows “the use of PI- or INSTI- vs NNRTI-based cART regimens, particularly those containing raltegravir, may confer greater risk of incident DM.” Investigators add that further research is required to identify patients at highest risk of metabolic complications, the mechanisms driving the observed risk differences, and appropriate risk-reducing interventions in this aging and increasingly overweight population.


Rebeiro PF, Jenkins CA, Bian A, et al. Risk of incident diabetes mellitus, weight gain, and their relationships with integrase inhibitor-based initial antiretroviral therapy among persons with HIV in the US and Canada. Published online September 16, 2020. Clin Infect Dis. doi:10.1093/cid/ciaa1403