Amanda Willig, PhD

For people who are HIV-positive (PWH), initiating ART with integrase strand transfer inhibitor (INSTI)-based versus non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens may present greater risk for incident diabetes mellitus (DM), according to findings presented at the 2023 Conference on Retroviruses and Opportunistic Infections.

This risk is likely only partially due to weight gain over the course of 12 months, the researchers noted.

In ART-naïve PWH initiating ART, INSTI-based regiments have been linked with greater weight gain, although metabolic consequences are unclear. Amanda Willig, PhD, and colleagues examined the impact of initial ART regimen class on incident DM and potential mediation of this effect by weight change in a large North American cohort of individuals with HIV.

Integrase Inhibitors Are ‘Preferred Part’ of First-Line HIV Treatment

“Diabetes prevalence continues to increase among adults with HIV,” says Dr. Willig. “While we know that HIV infection itself, genetic risk, and other lifestyle factors (poor diet and low physical activity), can increase diabetes risk, it is less clear whether newer ART regimens such as integrase inhibitors also contribute to diabetes risk. This question is important, because integrase inhibitors are often a preferred part of first-line regimens for HIV treatment. Understanding how various ART classes impact diabetes risk will allow providers to appropriately tailor regimens based on an individual patient’s risk factor and provide appropriate prevention strategies, such as nutrition counseling and medical management of diabetes.”

The study team included treatment-naïve adults initiating INSTI-, NNRTI- or protease inhibitor (PI)-based ART from January 2007 through December 2016 with 12-month (±6 months) weight measurements in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).

The researchers followed individuals until incident DM (A1C >6.5%, initiation of diabetes-specific medication, or DM diagnosis along with diabetes-related medication precluding prevalent DM or pre-diabetes, core regimen change, administrative close, virologic failure (≥400 copies/mL), death, or loss to follow-up.

Raltegravir Specifically Associated With Higher Incident Diabetes

Among 16,305 eligible patients, 50% started NNRTIs, 32% started PIs, and 19% started INSTIs, with median follow-up periods of 3.3, 2.8, and 2.1 years, respectively. Of all INSTI initiators, 52% started elvitegravir, 30% raltegravir, and 18% dolutegravir.

Overall, 2% of participants (N=333) developed DM. Tenofovir alafenamide was part of less than 1% of regimens. Those starting INSTIs compared with NNRTIs had a greater risk for incident DM (HR=1.30), greater than PI versus NNRTI initiators (HR=1.07). Mediation analysis showed an INSTI-DM association that was attenuated by 5% (HR=1.24) with inclusion of 12-month weight measurements in the full model.

“After controlling for other factors that can increase diabetes risk in HIV, we found that use of a protease inhibitor or integrase inhibitor—specifically raltegravir—was associated with increased incident diabetes,” Dr. Willig says. “It is important to note that not all integrase inhibitors were associated with diabetes risk, and that other modifiable risk factors—including CD4+ T cell count, initial body weight, and weight gain following treatment—were also linked with diabetes risk.”

Dr. Willig and colleagues add that additional studies are needed to determine if any integrase inhibitor regimens are associated with diabetes in those with HIV, and if so, what may be causing this increased risk. “Providers can use this information to proactively support patients in behaviors that reduce diabetes risk when certain ART regimens are prescribed,” Dr. Willig says.