Predicted diabetes risk with first-line ART regimens: results from the ADVANCE trial
Polly Clayden, HIV i-Base
Increased risk of diabetes predicted for people receiving tenofovir alafenamide (TAF), emtricitabine (FTC) and dolutegravir (DTG) in the ADVANCE trial – according to an analysis presented at CROI 2020. 
In ADVANCE 1053 treatment-naive people in South Africa were randomised to one of three first-line ART regimens. More participants taking first-line TAF/FTC/DTG developed clinical obesity compared to tenofovir disoproxil fumarate (TDF)/FTC/DTG and TDF/FTC/efavirenz (EFV). 
The analysis of predicted risks associated with obesity in the study set out to answer the following research questions:
- What changes are seen in markers of cardiovascular risk and diabetes?
- Can we use risk equations to predict the risk of cardiovascular disease or diabetes from these changes?
At baseline characteristics were balanced across the three study arms, participants were 99% black and 59% women. The median age was 31 years, approximately 20% had viral load above 100,000 copies/mL and CD4 was about 350 cells/mm3.
Women weighed more and had higher BMI than men: approximately 27 vs 21 kg/m2. Just over half the participants had a normal BMI at baseline, and approximately a quarter were overweight.
Mean change in weight at week 96 was greater in women than men. Mean weight increase for women in the TAF/FTC/DTG, TDF/FTC/DTG and TDF/FTC/EFV arms was 8 kg, 5 kg and 3 kg, respectively. For men, mean weight increase for the respective regimens was 5 kg, 4 kg and 1 kg.
Treatment-emergent obesity occurred in 28%, 17% and 12% of women in the TAF/FTC/DTG, TDF/FTC/DTG and TDF/FTC/EFV arms, respectively. Compared to 7%, 5% and 3% of men in the respective treatment arms.
There was less increase in cholesterol in the TDF/FTC/DTG arm than in the other two arms (see Table 1). Total cholesterol and LDL increased in the TAF/FTC/DTG arm. Fasting glucose increased more in the TDF/FTC/EFV arm than the other two.
Table 1: Changes in laboratory parameters to week 96: median (IQR)
regimen / comparison
|1.TAF / FTC / DTG
|2.TDF / FTC / DTG
|3.TDF / FTC / EFV
1 vs 3
1 vs 2
2 vs 3
|Total cholesterol (mg/dL)||10.4
(-5.4 to 24)
(-13 to 19.7)
(-1.9 to 33.3)
(-6.2 to 20.5)
(-10.8 to 12.4)
(-5.0 to 22.0)
(-2.3 to 12.0)
(-2.3 to 12)
(2.3 to 19.3)
|Fasting glucose (mg/dL)||19.3
(7.7 to 34.8)
(0.0 to 34.8)
(11.6 to 42.5)
|Systolic BP (mmHg)||3.0
(-7.0 to 11.0)
(-12.0 to 8.0)
(-9.0 to 8.0)
Metabolic syndrome (International Diabetes Federation definition – clinical obesity plus at least two of: raised triglycerides; reduced HDL cholesterol; raised blood pressure; raised fasting glucose) emerged in 8%, 6% and 3% of participants in the TAF/FTC/DTG, TDF/FTC/DTG and TDF/FTC/EFV arms respectively. There were statistically significant differences between TAF/FTC/DTG and TDF/FTC/DTG at week 96 (p=0.031).
The investigators used three risk equations to calculate the risk of cardiovascular events or diabetes in ADVANCE participants.
The Framingham risk equation estimates the 10-year risk of heart attack or coronary death. According to this equation, the investigators reported no significant difference and low risk across arms at baseline: 2.37%, 2.53% and 2.24% in the TAF/FTC/DTG, TDF/FTC/DTG and TDF/FTC/EFV arms respectively.
At week 96 there was a similar and very modest increase in risk: +0.43%, +0.22% and +0.28 across the respective treatment arms.
The QRISK equation estimates the 10-year risk of developing heart attack or stroke. This equation looks at a larger number of variables than Framingham – including black African ethnicity.
According to QRISK, the baseline 10-year risk of heart attack or stroke was very low: 0.6%, 0.6% and 0.5% in the TAF/FTC/DTG, TDF/FTC/DTG and TDF/FTC/EFV arms respectively.
At week 96 there was a slightly lower borderline significant risk with TDF/FTC/EFV compared with TAF/FTC/DTG (p=0.027)
The QDiabetes score estimates the 10-year risk of developing diabetes. Black African ethnicity is also included among the variables in this equation.
The baseline 10 year risk score of developing diabetes was: 0.30%, 0.40% and 0.30% in the TAF/FTC/DTG, TDF/FTC/DTG and TDF/FTC/EFV arms respectively.
At week 96, this increased to 0.90%, 0.50% and 0.70% in the respective arms. Compared with TDF/FTC/DTG, the risk of diabetes was significantly higher with TAF/FTC/DTG (p=0.004) and with TDF/FTC/EFV (p=0.005). There were no significant differences between TAF/FTC/DTG and TDF/FTC/EFV.
The investigators noted that among women treated with TAF/FTC/DTG, weight is continuing to increase, with no sign of a plateau. The predictive models do not account for additional weight gain after week 96.
There is very little additional risk of MI in this young population, but there is a significant increase in the predicted risk of diabetes for people taking TAF/FTC/DTG vs TDF/FTC/DTG.
For every 1000 people treated, these results suggest that an additional 4 people taking TAF/FTC/DTG would develop diabetes. The investigators have checked these results using another predictive equation (Cambridge algorithm) and seen the same.
In South Africa, with its vast HIV epidemic, this would translate into large numbers of additional diabetes cases.
WHO 2019 guidelines recommend TDF/FTC/DTG as first-line treatment. TAF/FTC/DTG is reserved only for special circumstances: people with osteoporosis or impaired renal function. The results from this analysis support the current WHO guidelines.
- Hill A et al. Risks of metabolic syndrome, diabetes, and cardiovascular disease in ADVANCE trial. CROI 2020. Boston, MA. 8–11 March 2020. Oral abstract 81.
- Clayden P. Weight gain and metabolic syndrome with dolutegravir and TAF: results from the ADVANCE trial. HTB. 15 November 2019.