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Switching from Lopinavir/ritonavir (Kaletra) to Boosted Atazanavir (Reyataz) Reduces Visceral Fat and Improves Glucose Metabolism

A recent study provides further evidence that atazanavir (Reyataz), even when boosted with ritonavir, is associated with fewer metabolic side effects than other protease inhibitors. At 6 months after switching from lopinavir/ritonavir (Kaletra) to atazanavir/ritonavir, participants had less belly fat, more muscle glucose uptake, and lower blood glucose levels than those who stayed on the former regimen.

Not long after the advent of HAART incorporating protease inhibitors (PIs), people with HIV and their clinicians began to report unusual metabolic complications including central fat accumulation, elevated blood lipid levels, and insulin resistance. These side effects are a concern because they raise the risk of cardiovascular disease.

The second-generation PI atazanavir tends to cause fewer metabolic toxicities than other drugs in its class, even when combined with a boosting dose of ritonavir. In a small study reported in the July 17, 2009 issue of AIDS, a research team from Massachusetts General Hospital and Harvard Medical School evaluated the effects of switching from lopinavir/ritonavir to atazanavir/ritonavir on muscle glucose uptake, glucose homeostasis, blood lipid levels, and body composition.

The analysis included 15 HIV positive men and women taking a regimen containing lopinavir/ritonavir who had evidence of hyperinsulinemia (elevated insulin levels) and/or dyslipidemia (abnormal lipid levels) at baseline. The participants were randomly assigned to either continue on lopinavir/ritonavir or switch to 300/100 mg daily atazanavir/ritonavir for 6 months.

The primary endpoint was change in thigh muscle glucose uptake as measured by positron emission tomography. Secondary endpoints included abdominal visceral adipose tissue (fat surrounding the internal organs), fasting lipid levels, and safety parameters.

Results

• After 6 months, anterior thigh muscle glucose uptake increased significantly in the atazanavir/ritonavir arm compared with the lopinavir/ritonavir arm (treatment effect +18.2 mcmol/kg/min; P = 0.035).
• Visceral adipose tissue area decreased significantly in patients who switched to atazanavir/ritonavir compared with those who stayed on lopinavir/ritonavir (-15.5% vs +10.8%; treatment effect -31 cm; P = 0.047).
• Switching to atazanavir/ritonavir significantly decreased levels of triglycerides (treatment effect -182 mg/dl; P = 0.02) and total cholesterol (treatment effect -23 mg/dl; P = 0.01).
• However, high-density lipoprotein (HDL or “good”) and low-density lipoprotein (LDL or “bad”) cholesterol levels did not change significantly.
• Fasting glucose also decreased significantly following the switch to atazanavir/ritonavir (treatment effect -15; P = 0.002).
• There was no overall change in immune function among patients who completed the study, but 1 person who switched to atazanavir/ritonavir experienced virological breakthrough.
• Bilirubin levels increased significantly in the atazanavir/ritonavir switch arm, but no patients had clinically significant elevations necessitating drug discontinuation.
• Likewise, there was a small but statistically significant increase in ALT in the atazanavir/ritonavir arm, but no one developed serious (grade 2-4 ) liver toxicity or discontinued therapy for this reason.

Based on these findings, the investigators concluded, “Switching from lopinavir/ritonavir to Atazanavir/ritonavir significantly increases glucose uptake by muscle, decreases abdominal visceral adipose tissue, improves lipid parameters, and decreases fasting glucose over 6 months.”

“Switching to atazanavir/ritonavir from lopinavir/ritonavir should only be considered in those patients who have stable virologic suppression and no contraindications to atazanavir, including hypersensitivity and the use of proton pump inhibitors or certain statins,” they elaborated in their discussion. “Moreover, any switch of antiretroviral therapy carries a risk of virologic failure and requires careful, frequent monitoring. For those patients who are virologically stable and are experiencing significant metabolic complications from HAART, however, our data suggest that a switch to Atazanavir/ritonavir may ameliorate cardiometabolic risk.”

“It is particularly significant that individuals in our study who switched to atazanavir/ritonavir demonstrated increased muscle glucose uptake in spite of continued ritonavir boosting,” they noted. “The ritonavir used for boosting, combined with the other [antiretrovirals] in our individuals' treatment regimens, may have diminished the overall improvement in insulin sensitivity.”

“To our knowledge, the significant decrease in visceral adipose tissue after switch to atazanavir/ritonavir has not been reported previously, and it is of a similar magnitude (-15%) to that observed in other studies with strategies such as growth hormone or growth hormone receptor hormone analogs,” they added.

Program in Nutritional Metabolism, Division of Infectious Diseases, and Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA; National Institutes of Health, Bethesda, MD.

7/10/09

Reference

TL Stanley, T Joy, CM Hadigan, and others. Effects of switching from lopinavir/ritonavir to atazanavir/ritonavir on muscle glucose uptake and visceral fat in HIV-infected patients. AIDS 23(11): 1349-1357. July 17, 2009.