HIV infection has been independently associated with insulin resistance (IR), potentially through chronic immune activation/inflammation, however this effect is not necessarily mitigated through successful antiretroviral therapy (ART). ART has been associated with IR through varying mechanisms, however, in the context of combination ART, increased obesity, and an aging HIV-infected population, these potential associations are difficult to interpret. We investigated potential risk factors associated with HOMA-IR (homeostasis model of assessment – insulin resistance) and the potential effect of dolutegravir (DTG) on IR over time.
Data from 4 DTG clinical trials (SPRING-1, STRIIVING, SWORD-1 and -2) with fasting insulin and glucose measurements available, were included; subjects with diabetes were excluded. IR was determined by HOMA mathematical model and defined as a HOMA-IR value ≥ 2; additional cut-offs of 3 and 4 were also explored. Analysis of relationship between baseline (BL) risk factors and HOMA-IR was completed. Change in HOMA-IR over time and relative to controls were assessed with logistic regression and ANCOVA models, respectively.
HOMA-IR data was available at BL, week 24 and week 48 for 824, 304 and 543 DTG-exposed subjects and 713, 219 and 460 control subjects, respectively. At BL, subjects were mostly male (81%), white (76%) and had a median age of 43yrs; 50% were overweight/obese; 70% had a HOMA-IR>2. Results are shown in the table. There were similar modest increases in HOMA-IR between DTG and control groups over time (24 and 48 weeks). Overall, there was no difference in the odds of HOMA-IR>2 between treatment groups at 48 weeks. An association between BL HOMA-IR and increasing age, geographic region, increased BMI/weight, the presence of metabolic or cardiac disorders, lipids, and elevated liver function tests (ALT, ALP and albumin) was observed. Risk factors for IR (HOMA-IR>2) at week 48 were BL HOMA-IR, Sex, BMI, AIDS CDC category, smoking history, and elevated ALT.
There was no association between treatment and insulin resistance observed in this analysis over a 48 week period, however IR modestly increased over time in all groups. In general, risk factors identified as being associated with IR at Week 48 were consistent with known risk factors for diabetes/IR. These results should be interpreted with caution as the studies were not primarily designed to assess effects of DTG exposure on insulin resistance.