Fat Gains After Starting HIV Treatment Associated With High Viral Loads

The fat gains experienced after going on antiretroviral therapy may not depend as much on the specific regimen as it depends on whether one had a high viral load before starting treatment, according to a study presented at CROI 2015, in Seattle, Washington.

The study, A5260s, presented by Grace McComsey, M.D., of the Case Western Reserve University, looked for differences in body composition changes in various body compartments (peripheral fat and subcutaneous adipose tissue [SAT], as well as central fat and lean body mass) in people living with HIV initiating treatment on one of two ritonavir (Norvir)-boosted protease inhibitors (atazanavir [Reyataz] or darunavir [Prezista]) or an integrase-based regimen over 96 weeks.

However, the study didn't find any fat gain differences based on treatment regimen. Instead, the researchers found associations with other factors that were present at baseline (when individuals went on treatment). Specifically, having a high viral load when starting treatment was most consistently associated with body composition changes after starting antiretroviral therapy.

"I think it was amazing -- regardless of the regimen that you look at, the fat gains were so much more, if you start with very high viral load, and if you adjust for the inflammation markers, viral load remained by itself associated with higher gains," said McComsey.

Background

Even though there has been a decline in the incidence of lipoatrophy (fat wasting) with the use of nucleoside or nucleotide analogue drugs that are more mitochondria-friendly, increased body fat (central adiposity or lipohypertrophy) continues to occur in people initiating antiretroviral therapy.

The pathogenesis of lipohypertrophy remains unclear. Initially, it was blamed on protease inhibitors, however, studies showed that switching off of protease inhibitors to either non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as efavirenz (Sustiva, Stocrin), or more recently to integrase inhibitors, did not significantly improve central fat. Although, in at least one study, the use of ritonavir-boosted atazanavir was associated with greater gains in both peripheral and central fat compared to the use of efavirenz. However, there had not been any well-powered studies comparing changes in body composition in people initiating protease inhibitors versus those starting on integrase inhibitors.

Therefore, McComsey and colleagues conducted A5260s, a metabolic and cardiovascular sub-study of A5257, which had enrolled more than 1,800 treatment-naive individuals living with HIV with a viral load of at least 1,000 copies/mL. The study had randomized individuals to three NNRTI-sparing regimens: tenofovir/emtricitabine (Truvada) with either atazanavir/ritonavir, darunavir/ritonavir, or raltegravir (Isentress). The participants were also stratified according to baseline viral load ≥ or < 100,000 copies/mL, or having a low or high Framingham 10-year risk score of coronary heart disease.

The sub-study included 328 participants, and had specific exclusion criteria: no known cardiovascular disease, no diabetes and no use of lipid-lowering agents. At baseline and at week 96, the sub-study participants underwent a DXA scan as well as a computed tomography (CT) of their visceral and subcutaneous abdominal fat.

At baseline, measurements were taken of leptin, adiponectin (which are both involved in fat metabolism and regulation) and selected inflammatory markers and monocyte activation markers (IL-6, hs-CRP, D-dimer, sCD14, sCD163).

Baseline Characteristics

The baseline characteristics of the study participants were very well balanced between the arms. The median age was 36; 90% of the participants were male and 40% were white non-Hispanic. About one third of participants were in the high viral load strata. The body mass index (BMI) median was 25, and the body composition at baseline was very similar to or in line with other U.S. treatment initiation studies in the era of starting antiretroviral therapy with a higher CD4 count, according to McComsey.

Results

Peripheral Fat

There were two measures of peripheral fat: limb fat by DXA and subcutaneous adipose tissue (SAT) by CT.

• Limb fat change at week 96: All three study arms led to significant increases from baseline to week 96, but there were no significant differences between the three arms.
  • atazanavir/ritonavir: 11%
  • raltegravir: 20%
  • darunavir/ritonavir: 14%
• SAT change at week 96: There were significant increases from baseline in all three study arms with no significant differences between regimens.
  • atazanavir/ritonavir: 23%
  • raltegravir: 25%
  • darunavir/ritonavir: 20%
• Proportion of participants with >10% and >20% limb fat loss at week 96: Overall, 16% to 18% lost at least 10%; and 6% to 8% lost 20% or more of their baseline limb fat with no significant differences between the arms.

Central Fat

There were two measures of central fat: trunk fat by DXA and visceral adipose tissue (VAT) by CT.

• Trunk fat at week 96: There were significant increases in all three arms from zero to 96 weeks, but no significant differences between the study arms.
  • atazanavir/ritonavir: 16%
  • raltegravir: 29%
  • darunavir/ritonavir: 21%
• VAT change at week 96: About a 30% increase from zero to 96 weeks in all three study arms with no significant differences.
  • atazanavir/ritonavir: 31%
  • raltegravir: 33%
  • darunavir/ritonavir: 29%