ADVANCE Trial Data Links Dolutegravir with Weight Gain in HIV

New data comparing treatment regimens with dolutegravir versus efavirenz shows the therapies safe and effective, but the 96-week results also raises a significant concern: weight gain.

Dolutegravir (Tivicay) is a second-generation integrase inhibitor that has come into common use in high-income countries in part because it has a higher genetic barrier to resistance and better tolerability than efavirenz (Sustiva). The ADVANCE Trial compared the safety and efficacy of dolutegravir (DTG) combined with emtricitabine (Emtriva) and either tenofovir disoproxil fumarate (Viread) or tenofovir alafenamide (Vemlidy) with efavirenz (EFZ) plus emtricitabine and tenofovir disoproxil fumarate.

The 48-week results, published last year, showed the DTG-based regimens were non-inferior to EFZ-based therapy, which was the standard of care in South Africa, where the study was conducted.

The new, 96-week results similarly showed that the DTG-based therapies perform well in a side-by-side comparison. The 1,053 people enrolled in the trial were split into equal groups and each group had similar rates of achieving a plasma HIV-1 RNA concentration of less than 50 copies/mL. The tenofovir alafenamide, emtricitabine, and DTG group saw 79% of patients achieve that endpoint; the tenofovir disoproxil fumarate, emtricitabine, and DTG group had a success rate of 78%; and the tenofovir disoproxil fumarate, emtricitabine, and EFV group met the endpoint in 74% of cases. The results were published in The Lancet HIV.

Willem D. F. Venter, PhD, the study’s corresponding author, told Contagion those results were expected.

“The trial, without the weight gain signal, would’ve been painfully boring and predictable,” said Venter, head of the South Africa-based Ezintsha research institute. “[M]aybe the only surprise was that the EFV arm performed so well, and that we saw no sleep disturbance on DTG.”

However, the weight gain Venter noted was striking. In the tenofovir alafenamide, emtricitabine, and DTG group, the mean weight gain was 7.1 kg. In the other DTG group, who received tenofovir disoproxil fumarate and emtricitabine, the mean weight gain was 4.3 kg. The tenofovir disoproxil fumarate, emtricitabine, and EFZ group had an average weight gain of 2.3 kg. Weight gain tended to be greater among women than men.

Venter noted that weight gain aligned with gains in visceral adipose tissue, which were considerably higher in the group given tenofovir alafenamide compared to the EFZ group. That’s concerning for a number of reasons, Venter and colleagues wrote.

“Excess visceral fat is associated with various cardio-metabolic risk factors, including elevated blood pressure, LDL cholesterol, insulin, and glucose and decreased HDL cholesterol,” the investigators wrote.

The authors noted that weight gain is sometimes written off as simply a consequence of the patient’s “return to health,” but he said the sustained weight gain noted in this study suggests a multi-factorial cause and one that requires further investigation.

“The weight gain issue raises complex cultural, ethical, and regulatory challenges for future clinical trials, especially with regard to stopping rules,” they said. For instance, if a patient is stopped from a therapy due to weight gain, it’s not clear that switching regimens would lead to a stoppage or reversal of the weight gain.

In a broader sense, the weight gain issue is more meaningful because it comes at a time when HIV is treated more like a chronic illness, rather than a “death sentence.” Such a shift means patients can live for decades with the virus, and their physicians must therefore ponder the long-term health implications of HIV treatment decisions.

Venter said he’s seen first-hand the shift in patients, comparing patients from an earlier era to “skeletons” due to their dramatic weight loss as a result of HIV. However, he said the pendulum has now swung such that excessive weight gain has become a concern in the HIV population.

“It’s incredible,” he said. “I treated skeletons in 2004. Now the HIV clinics look like diabetic clinics! Never in my wildest projections did I think this is the way things would go.”