In the ADVANCE study, treatment with dolutegravir+tenofovir alafenamide+emtricitabine was associated with a higher risk of obesity, metabolic syndrome, increase in visceral and subcutaneous fat, and long-term risk of developing diabetes, when juxtaposed to comparative therapies. These results were presented by Andrew Hill, University of Liverpool (UK), at the virtual CROI in March 2020.
Obesity (BMI > 30) can shorten life expectancy as it is a risk factor for cardiovascular diseases such as heart attack, stroke, Alzheimer's disease or cancer. Using the data from the ADVANCE study, Hill and his colleagues investigated what changes had occurred in markers for cardiovascular risk and diabetes and whether these changes could be used to estimate the long-term risk of cardiovascular disease and diabetes.
The open-label South African ADVANCE study included 1,053 HIV patients who were randomized to receive treatment with dolutegravir/tenofovir alafenamide/emtricitabine (DTG/TAF/FTC, n = 351) or dolutegravir/tenofovir disoproxil fumarate/emtricitabine (DTG/TDF/FTC, n = 351) for 96 weeks. The control group received efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC, n = 351). The test subjects were 32 years old on average, almost 60% were women. Almost all patients were black Africans. At the start of the study, most of the patients had a normal body weight. About 11% were underweight, 12% obese.
After 96 weeks, the test subjects had clearly gained weight under dolutegravir and especially under dolutegravir + tenofovir alafenamide. Bodyweight increased much more in women than in men. Under DTG/TAF/FTC 28% of the women and 7% of the men developed obesity, under DTG/TDF/FTC 17% of the women and 5% of the men and in the comparison group, 12% of the women and 3% of the men developed obesity.
Under DTG/TAF/FTC, total cholesterol levels increased by 10.4 mg/dl, under DTG/TDF/FTC by 1.5 mg/dl and under EFV/TDF/FTC by 13.1 mg/dl, while LDL (low-density lipoprotein) cholesterol levels rose by 8.5 mg/dl, 2.3 mg/dl and 6.2 mg/dl respectively. The fasting blood glucose levels were 19.3, 19.3 and 271 mg/dl respectively.
A DEXA (Dual-energy X-ray absorptiometry) scan showed that visceral and subcutaneous fat tissue in the DTG/TAF/FTC group increased significantly more in percentage terms than in the other two groups.
A therapy-associated metabolic syndrome was detected after 96 weeks in 8% of the DTG/TAF/FTC group, 6% of the DTG/TDF/FTC group and 3% of the comparison group.
The Framingham risk score (FRS) estimate was used to assess the 10-year risk of heart attack or coronary death. There was no significant difference between the three therapy arms. After 96 weeks of treatment, the 10-year risk increased by 0.43% in the DTG/TAF/FTC group, by 0.22% in the DTG/TDF/FTC group and by 0.28% in the EFV/TDF/FTC group.
The 10-year risk for a cardiac event or stroke, using the QRISK estimate, showed borderline significant differences (0 = 0.027) between DTG/TAF/FTC treatment over 96 weeks (+ 0.20%) and the comparison group (0.10%).
The 10-year risk of developing diabetes was assessed with the QDIABETES estimate. There were significant differences between DTG/TAF/FTC and the control group at 48 weeks of treatment (+ 0.70% versus + 0.60%; p = 0.008) and at 96 weeks of treatment (+ 0.90% versus + 0.70%; p = 0.004) and between the control group and the DTG/TDF/FTC group at 48 weeks of treatment (0.60% versus 0.40%; p = 0.047) and at 96 weeks of treatment (0.70% versus 0.50%; p = 0.005).
However, Hill pointed out that the study population was median young at 32 years of age, at which age the risk of heart attack and diabetes is relatively low. In addition, especially in women in the DTG/TAF/FTC group, bodyweight increased continuously until week 96 and had not yet reached a plateau at that time. However, the predictive model does not take into account further weight gain after week 96. The analyses should be repeated with the results of further studies.
Hill A, et al Risks of metabolic syndrome, diabetes, and cardiovascular disease in ADVANCE trial. Virtual CROI 2020, Abstract 81. https://www.croiconference.org/sessions/risks-metabolic-syndrome-diabetes-and-cardiovascular-disease-advance-trial