Dolutegravir (Tivicay, also found in Triumeq and Dovato) and raltegravir (Isentress), both integrase inhibitors commonly used in HIV regimens, may change the structure of fat cells and could cause insulin resistance, French researchers reported at the 17th European AIDS Conference in Basel, Switzerland.
The researchers studied cells from people living with HIV who had been taking dolutegravir or raltegravir. Previous studies have suggested that people taking an integrase inhibitor were more likely to gain weight, but until now it’s been unclear exactly why or how.
Basically, it all comes down to the two kinds of fat tissue: brown fat (a.k.a. visceral fat), which collects around organs and in the abdomen; and white, or subcutaneous, fat, which collects just beneath the skin.
Researchers found that dolutegravir and raltegravir can both have a direct effect on these fat tissues because they are associated with lower levels of leptin, a hormone that decreases the appetite, and adiponectin, a hormone that manages how our cells store glucose, a primary source of energy.
After studying two groups of monkeys—where one group was on a regimen of either dolutegravir, tenofovir, and emtricitabine; or raltegravir, tenofovir, and emtricitabine; and another group was untreated—researchers found greater fibrosis (or a high formation of excess tissue) in fat tissue in the monkeys that were exposed to antiretroviral therapy.
When it came to humans, researchers analyzed samples of fat cells from 14 people living with HIV, some who were taking integrase inhibitors and some who were not. The fat cells were collected when the people underwent weight-loss surgery.
The data showed that 80 percent of the subjects had fibrosis in their subcutaneous fat tissue and 70 percent of those on integrase inhibitors had fibrosis in their visceral fat tissue. Some scientists believe fibrosis contributes to insulin resistance, which can cause diabetes and heart disease.
To better understand the impact integrase inhibitors have on fat cells, researchers looked at adipose (fat) stem cells collected from HIV-negative women. The scientists found that cells exposed to dolutegravir or raltegravir in the laboratory produced more of the types of collagen associated with obesity and with fibrosis in adipocytes, a specialized type of fat cell. The drugs were also associated with a greater production of fat cells and lipid storage, and with lower levels of leptin and lower uptake of glucose.
A previous review of literature in JCI Insight noted that fibrosis within the adipose tissue might influence the development of obesity or obesity-related comorbidities, but that connection has not yet been proven conclusively. There is no scientific consensus about whether such fibrosis causes or contributes to obesity or is a result of being overweight. The 2018 piece called for additional research.
The more recent study adds to our understanding of how two integrase inhibitors impact adipose tissue. It may not prove that the changes the integrase inhibitors cause in fat cells are the drivers of the weight gain associated with the drugs, but the results do suggest that there is a correlation.
The authors concluded, “We demonstrate here for the first time…that INSTI [integrase inhibitors] exert a direct impact on adipose tissue adipogenesis, fibrosis and insulin resistance. These results, which reveal the adipose tissue toxicity of dolutegravir and raltegravir, are important to explain fat modifications reported in INSTI-treated HIV-infected patients.”