The integrase inhibitors dolutegravir (Tivicay, also in Triumeq and Dovato) and raltegravir (Isentress) cause changes in the structure of fat cells that may promote obesity, and can cause insulin resistance, studies of cells sampled from people living with HIV and monkeys exposed to the drugs have found. The findings were presented by Jennier Gorwood at the Sorbonne Universté INSERM UMRS 938 Saint‐Antoine research centre in Paris, at the 17th European AIDS Conference (EACS 2019) in Basel, Switzerland.
Some cohort studies and clinical trials have shown that after starting antiretroviral treatment, people taking an integrase inhibitor were more likely to gain weight and more likely to experience substantial weight gain. However, it has been unclear how integrase inhibitors might interfere with metabolism and cause fat gain.
The French research group presented evidence that the integrase inhibitors dolutegravir and raltegravir have direct effects on adipose tissue that could promote weight gain. There are two types of fat tissue, or adipose tissue: visceral fat or brown fat, which accumulates around organs and in the abdomen, and subcutaneous fat or white fat, which accumulates beneath the skin.
The cells which make up fat tissue – adipocytes – are programmed to store fat and send signals that govern fat storage through the hormones leptin (which down-regulates fat storage by reducing appetite) and adiponectin (which governs glucose uptake by cells). Fat tissue was sampled from five cynomolgus monkeys, 15 days after commencing a regimen either of dolutegravir, tenofovir and emtricitabine, or raltegravir, tenofovir and emtricitabine. Tissue was also sampled from nine untreated monkeys who served as a control group.
The researchers found: significantly greater fibrosis in subcutaneous and visceral fat tissue of monkeys exposed to antiretroviral therapy (ART); peri-adipocyte fibrosis in monkeys, which is associated with metabolic syndrome; and larger adipocytes and markers of new adipocyte formation (adipogenesis) in monkeys exposed to ART.
The researchers then analysed samples of subcutaneous and visceral fat from 14 people receiving either an integrase inhibitor-containing antiretroviral regimen or an integrase-sparing regimen. This group of people were all extremely obese and tissue was sampled at the time of bariatric surgery, undergone to promote weight loss.
The researchers found: ibrosis in subcutaneous fat tissue of approximately 80% of people on ART, regardless of regimen; a greater frequency of fibrosis in visceral fat tissue among people treated with integrase inhibitors (approximately 70% showed peri-adipocyte fibrosis); to examine whether integrase inhibitors have direct effects on fat cells, human adipose stem cells from HIV-negative women were exposed in the laboratory to dolutegravir or raltegravir before and during the process of differentiation into adipocytes. Exposure to the drugs was associated with greater production of collagen types associated with adipocyte fibrosis and obesity; dolutegravir or raltegravir exposure was associated with greater adipocyte differentiation and greater expression of markers associated with lipid storage. Cells exposed to dolutegravir or raltegravir had higher levels of lipid accumulation, lower levels of leptin and adiponectin and lower uptake of glucose compared to control samples.
This picture of adipocyte fibrosis and dysfunction suggests a possible pathway for weight gain during integrase inhibitor treatment, said Gorwood. Dolutegravir has been shown to inhibit melanocyte-stimulating hormone (MSH), which controls appetite. Lower HSH activity has been associated with the development of obesity.
Opinions vary among metabolic researchers regarding the significance of adipocyte fibrosis. Fibrosis may be a consequence of chronic inflammation prompted by a chronic excess of energy from food. It may be a critical step in the development of insulin resistance, in the view of some researchers.
But much is still to be learnt about the cellular pathways leading to obesity and insulin resistance, another French research group pointed out in 2013, indicating that these findings are preliminary and suggestive of further avenues for research rather than proof of a mechanism by which integrase inhibitors cause weight gain.
Purpose: There is growing evidence that integrase inhibitors (INSTI) dolutegravir and raltegravir promote peripheral and central adipose tissue/weight gain in HIV‐infected individuals, but the mechanisms involved remain unknown. We aimed to assess the effect of these molecules on adipose tissue morphology, function and metabolism.
Method: Morphology and function of subcutaneous (SCAT) and visceral adipose tissue (VAT) were studied in: ‐HIV‐infected patients from the ObeVIH study, at the time of bariatric surgery (BMI 41.8 kg/m2): 14 patients received INSTI (10 dolutegravir, 2 raltegravir, 2 elvitegravir) and 5 an INSTI‐sparing regimen.
‐Uninfected cynomolgus macaques treated or not 15 days with dolutegravir/tenofovir/emtricitabine.
Human Adipose Stem Cells (ASCs) were chronically treated with dolutegravir or raltegravir before or during adipogenesis. Adipogenic capacities, insulin response and extracellular matrix component expression were analyzed.
Results: SCAT from the ObeVIH patients presented peri‐lobular and peri‐adipocyte fibrosis in most samples. Conversely, VAT of INSTI‐treated patient presented a higher level of peri‐adipocyte fibrosis than that of non‐INSTI‐treated patients.
Dolutegravir‐treated macaques presented a higher level of fibrosis and an increased adipocyte size in both SCAT and VAT, when compared to untreated macaques. Adipogenic marker expression was increased in SCAT and VAT, whereas adiponectin expression was decreased in SCAT, suggesting that, despite a pro‐adipogenic effect, dolutegravir may favor insulin resistance.
In ASCs, INSTI‐treatment increased collagen 1 and 6 and a‐smooth‐muscle‐actin expression indicating a pro‐fibrotic effect. In ASC‐differentiated adipocytes, dolutegravir, and to a lesser extent raltegravir, increased lipid accumulation and adipogenic marker expression, decreased adiponectin expression and induced insulin resistance.
Conclusion: We demonstrate here for the first time, by using in vivo and in vitro complementary models, that INSTI 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.
J Gorwood, C Bourgeois, V Pourcher, F Charlotte, G Pourcher, M Mantecon, C Rose, R Morichon, R Le Grand, C Katlama, B Fève, O Lambotte, J Capeau, V Béréziat, C Lagathu
[link url="http://www.aidsmap.com/news/nov-2019/dolutegravir-and-raltegravir-cause-changes-fat-cells"]Aidsmap material[/link]
[link url="https://onlinelibrary.wiley.com/doi/full/10.1111/hiv.12814"]EACS 2019 abstract book[/link]