Risk of Incident Diabetes Mellitus, Weight Gain, and Their Relationships With Integrase Inhibitor–Based Initial Antiretroviral Therapy Among Persons With Human Immunodeficiency Virus in the United States and Canada

Abstract

Background Integrase strand transfer inhibitor (INSTI)–based combination antiretroviral therapy (cART) is associated with greater weight gain among persons with human immunodeficiency virus (HIV), though metabolic consequences, such as diabetes mellitus (DM), are unclear. We examined the impact of initial cART regimen and weight on incident DM in a large North American HIV cohort (NA-ACCORD). Methods cART-naive adults (≥18 years) initiating INSTI-, protease inhibitor (PI)–, or nonnucleoside reverse transcriptase inhibitor (NNRTI)–based regimens from January 2007 through December 2017 who had weight measured 12 (±6) months after treatment initiation contributed time until clinical DM, virologic failure, cART regimen switch, administrative close, death, or loss to follow-up. Multivariable Cox regression yielded adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident DM by cART class. Mediation analyses, with 12-month weight as mediator, similarly adjusted for all covariates. Results Among 22 884 eligible individuals, 47% started NNRTI-, 30% PI-, and 23% INSTI-based cART with median follow-up of 3.0, 2.3, and 1.6 years, respectively. Overall, 722 (3%) developed DM. Persons starting INSTIs vs NNRTIs had incident DM risk (HR, 1.17 [95% CI, .92–1.48]), similar to PI vs NNRTI initiators (HR, 1.27 [95% CI, 1.07–1.51]). This effect was most pronounced for raltegravir (HR, 1.42 [95% CI, 1.06–1.91]) vs NNRTI initiators. The INSTI–DM association was attenuated (HR, 1.03 [95% CI, .71–1.49] vs NNRTIs) when accounting for 12-month weight. Conclusions Initiating first cART regimens with INSTIs or PIs vs NNRTIs may confer greater risk of DM, likely mediated through weight gain.

Contribution of Adipose Tissue to the Chronic Immune Activation and Inflammation Associated With HIV Infection and Its Treatment

“…The association between INSTI and diabetes was attenuated by accounting for 12-month weight gain. Initiating combination ART regimens with INSTIs or PIs + NNRTIs may confer a greater risk of diabetes; this is probably mediated by weight gain (196). In the French DAT'AIDS study, 265 of the 19,462 HIV-infected patients initiating ART developed diabetes.…”

Bictegravir-Based Antiretroviral Therapy-Associated Accelerated Hyperglycemia and Diabetes Mellitus

“…Although early ART regimens were associated with dyslipidemia and other metabolic derangements, contemporary ART, including the integrase strand transfer inhibitor (INSTI) class, are thought to have a better safety profile. Recent data has suggested that INSTI use may be associated with weight gain and the development of insulin-resistant diabetes [ 2 , 3 ] and, in rarer cases, accelerated hyperglycemia [ 4–6 ]. Bictegravir (BIC) is a second-generation INSTI, available in coformulation with emtricitabine (FTC) and tenofovir alafenamide (TAF), and is currently recommended as a first-line ART regimen for newly diagnosed PWH [ 7 , 8 ].…”

An observational study of the prevalence of metabolic syndrome in treatment-experienced people living with HIV in Singapore

“…The median duration of exposure for PLHIV who had ever received INSTIs was shorter than for those on PIs. Data from a large North American HIV cohort suggested that initiation of first cART regimens with INSTIs versus NNRTIs may confer an increased risk of incident diabetes, likely mediated through weight gain [ 46 ]. Studies have found weight gain following a switch to INSTIs, with more pronounced increases in HIV-positive women and with the use of dolutegravir [ 47 – 52 ].…”