Cardiovascular Risk Unclear for HIV Patients on Dolutegravir

Heather Boerner

October 30, 2018

GLASGOW — Patients with HIV who switched to a dolutegravir-based regimen from a ritonavir-boosted protease inhibitor regimen experienced body mass gain and changes in biomarkers related to increased insulin resistance, according to a subanalysis of the NEAT 022 study (NCT02098837).

These changes present clinicians with a "mixed message" about the cardiovascular benefit of dolutegravir because previous data have shown an overall cardiovascular benefit, including a drop in oxidized low-density lipoprotein, said Esteban Martinez, MD, PhD, from the University of Barcelona, who presented the data here at HIV Drug Therapy 2018.

But the new data made Peter Reiss, MD, from the University of Amsterdam, who was not involved in the study, question whether the overall impact of dolutegravir on heart disease is positive.

"Martinez said in one of his slides that the NEAT 022 trial [AIDS. 2017;31:2503-2514] already showed that there's a cardiovascular benefit, but I don't think it did," given these biomarkers, said Reiss, who is a member of the Data Collection on Adverse Events in Anti-HIV Drugs (D:A:D) Study group.

Instead, this study points to the "complexity" of the newer class of HIV drugs on cardiovascular health, he added. "You can't draw any conclusions" until these biomarker signals are borne out in clinical studies.

Adiponectin and sCD14

Earlier findings from the main NEAT 022 study stand, of course: people who are virally suppressed on ritonavir-boosted protease inhibitor regimens maintained that suppression when they switched to dolutegravir-based regimens, with improved total cholesterol. And other studies have shown that dolutegravir leads to fewer drug-resistant mutations and better outcomes than efavirenz and ritonavir-boosted darunavir or atazanavir, both protease inhibitors.

But Martinez and his colleagues wanted to take a deeper dive into the larger lipid profiles. So they went back to the data on the 415 participants — most of whom were white men older than 50 years with high CD4 T-cell counts and at high risk for cardiovascular disease on the basis of their Framingham Coronary Heart Disease Risk Score. At 48 weeks, researchers tested plasma, serum, and urine from participants for a broad swath of biomarkers for cardiovascular disease, from highly sensitive C-reactive protein (hsCRP) for inflammation to oxidized low-density lipoprotein for oxidation to N-terminal pro b-type natriuretic peptide for heart failure. In addition, adiponectin as a marker for insulin resistance was tested, as was soluble CD14 (sCD14) as a marker of immune activation

Most of the markers didn't shift dramatically between the dolutegravir and protease-inhibitor regimens. But adiponectin and sCD14 did.

Table. Changes From Baseline in the Two Regimens at 48 Weeks
Marker Dolutegravir-Based Regimen,% Ritonavir-Boosted Protease Inhibitor Regimen, % P Value
Adiponectin –11 1 <.001
sCD14 –11 0 <.001

The shifts in adiponectin and sCD14 were associated with the other shifts. As sCD14 dropped, CD4 counts rose by a median of 32 cells/µL. And adiponectin dropped, body mass index (BMI) rose.

"Some of these changes are clearly good," Martinez told Medscape Medical News. "But some others — the decrease in adiponectin — were not because these patients were already borderline overweight."

And the decrease in adiponectin and sCD14 did not seem to be connected, "so the mechanism must be different," he said.

Whether that increase in weight will manifest as increased rates of diabetes or more symptoms of heart disease is unclear, he noted. However, as researchers continue to investigate the relation between integrase inhibitors, such as dolutegravir, and weight gain, providers might want to monitor BMI in older patients at high risk for cardiovascular disease.

"Weight change can be for the good or for the bad," said Martinez. "Some changes in weight can be beneficial. But others, for people who are already overweight or obese, may be detrimental."

Now it's not loss of fat, it's gain of fat that may be drug related.

The meaning of biomarker changes cannot be known until more studies come out. It is likely that this will be a continued topic of conversation at the Conference on Retroviruses and Opportunistic Infections next year, Reiss said.

"The clinical question is, what does it all mean? And where's the balance? I think without clinical outcomes, there's no way of saying," he explained. But, he added, the conversation might revive one that disappeared years ago.

Lipodystrophy was a major issue years ago when HIV drugs caused a redistribution of fat in noticeable ways. "We may be having a re-emergence of interest in fat tissue," he said. "Now it's not loss of fat, it's gain of fat that may be drug related. I think it needs to be studied."

NEAT 022 was funded by NEAT-ID and ViiV Healthcare. Martinez reports receiving honoraria from ViiV Healthcare, MSD, Gilead, and Janssen. Reiss has disclosed no relevant financial relationships.

HIV Drug Treatment 2018: Abstract O113. Presented October 29, 2018.

Follow Medscape on Twitter @Medscape and Heather Boerner @HeatherBoerner

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