Cumulative exposure to the nucleoside analogues (NRTIs) lamivudine (3TC, Epivir) and stavudine (d4T, Zerit) is associated with the development of insulin resistance, according to a prospective analysis of the Multicentre AIDS Cohort Study (MACS). This study of US men concurs with findings reported earlier this year from a US women's study that there is no association between insulin resistance and protease inhibitors (PIs), but also finds that there is no association between insulin resistance and non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs). In addition, nadir CD4 cell count was found to be associated with insulin resistance for the first time.
Abnormalities in glucose metabolism are part of the broader metabolic syndrome that itself comes under the umbrella term, lipodystrophy. Hyperglycaemia (or high blood sugar), defined as when glucose levels are greater than 5 mmol/l, is a sign of early glucose metabolism abnormalities.
The next stage is insulin resistance, defined in this study as fasting insulin levels greater than 15µU/ml, and confirmed by a calculation of QUICKI: a ratio of insulin-to-glucose levels, where a lower level suggests more insulin resistance. Untreated insulin resistance can result in diabetes, which is associated with a higher risk of cardiovascular disease, amongst other co-morbidities.
Investigators from MACS sites in four US cities sought to identify factors that may be associated with markers of insulin resistance. They collected demographic, antiretroviral and HIV-infection history in 1408 MACS enrolees that had fasting glucose and insulin measures out of the 1799 MACS enrolees that had a study visit between April 1999 and March 2003. They excluded 120 men who were taking medications that affect insulin levels, notably insulin, resulting in a sample study of 1288 men.
Of the 1288 men, 533 were HIV-positive and 755 were HIV-negative at the start of the study. Compared with the HIV-negative men, the HIV-positive men were younger (median 46 vs. 50 years; p
Short-term exposure (i.e. exposure in the previous six months) to any anti-HIV regimen was found to result in significantly lower QUICKI values compared with the HIV-negative group. However, although those who received PI-based HAART had the largest decline in QUICKI scores (-0.68), these were not statistically significantly lower than non-PI-HAART (-0.57; p=0.369) or mono-or dual therapy (-0.45; p=0.127). A similar non-significant association was seen when fasting hyperinsulinaemia was measured.
Although there was only a five percent difference in QUICKI scores between those on PI-based HAART and HIV-negative men, and this difference appears to be "seemingly modest", the investigators suggest that the difference "may be clinically important because of [insulin resistance's] potential association with diabetes and atherosclerosis." For example, in HIV-negative studies a six percent difference in QUICKI scores led to an eight-fold increased risk of developing type 2 diabetes over five years.
However, after analysing the effects of cumulative exposure to antiretroviral therapy by drug class (and adjusting for use of other drug classes), only cumulative exposure to nucleoside analogue reverse transcriptase inhibitors (NRTIs) was significantly and independently associated with both lower QUICKI values and increased odds of fasting hyperinsulinaemia. Over time, "cumulative exposure to PI drugs as a class showed no increased risk of elevated insulin resistance markers," the investigators write.
Within the nucleoside analogue class only two of the four drugs included in the analysis were associated with insulin resistance. Specifically, mean QUICKI values for men on 3TC were -0.06 (range -0.12 to 0.00) and on d4T were -0.11 (-0.17 to -0.05; both p
Notably, 3TC (61%) and d4T (41%) were the most commonly prescribed drugs of any class at the start of the study. But although 26% were receiving AZT (zidovudine, Retrovir) and 17% were receiving ddI (didanosine, Videx/VidexEC), neither were found to be associated with insulin resistance.
The most commonly prescribed PI, indinavir (Crixivan) (26%), was the only PI associated with any measure of insulin resistance - increased odds of hyperinsulinaemia for each cumulative year of exposure of 1.14 (95% CI, 1.02-1.26). However, it was not associated with a lower QUICKI score.
The investigators also found non-antiretroviral factors to be associated with insulin resistance. Although increasing age and increasing BMI were not surprising findings, they also found that nadir CD4 cell count (per 50 cells decrease) was significantly associated with lower QUICKI scores (-0.05 (-0.08 to -0.02; p
The investigators conclude by reiterating, that "cumulative exposure to NRTIs, but not PIs or NNRTIs, was independently associated with two markers of insulin resistance. These findings highlight the fact that insulin resistance in HIV-infected persons is attributable to other factors besides the use of PIs, including disease-related factors."
Brown T et al. Cumulative exposure to nucleoside analogue reverse transcriptase inhibitors is associated with insulin resistance markers in the Multicenter AIDS Cohort Study. AIDS 19 (13): 1375-1383, 2005.