The use of the boosted protease inhibitor Kaletra (lopinavir/ritonavir) causes an increase in triglyceride and total cholesterol levels, according to a Spanish study which monitored blood lipids in individuals taking the drug after an overnight fast. However, the study found fewer Kaletra-treated individuals with elevated blood lipids than were found in the clinical trials which led to the drug’s approval, and the investigators found that the strongest risk factor for the development of abnormal lipids whilst taking Kaletra was the presence of elevated blood fats when treatment with the drug was commenced. The study is published in the April 1st edition of Clinical Infectious Diseases, and is now available on-line.
In the Kaletra clinical trials, clinically significant increases in triglyceride and cholesterol levels were seen in approximately 10% of protease inhibitor-naïve individuals, in 25% - 30% of patients who had been treated with one protease inhibitor prior to taking Kaletra, and in up to 40% of patients who had taken multiple protease inhibitors before Kaletra. Spanish investigators were concerned that these studies did not look at blood lipid levels in patients after an overnight fast, a more reliable method of measuring blood lipids, and could therefore have overestimated the incidence of metabolic abnormalities in individuals taking Kaletra.
Accordingly, 348 patients starting Kaletra between autumn 2000 and spring 2002 were studied to see what impact initiating therapy with the drug had on their glucose, triglyceride, total cholesterol and HDL cholesterol levels. At three-monthly intervals, individuals had their lipid level, CD4 cell count and HIV viral load measured after an overnight fast.
The investigators also wished to see if any particular factors were associated with the risk of elevated lipids during treatment with Kaletra. These included age, sex, mode of HIV transmission, alcohol consumption, diabetes, body fat changes caused by HAART, the use of a protease inhibitor before Kaletra, and the use of lipid-lowering drugs at baseline.
At baseline, individuals treated with a protease inhibitor before starting therapy with Kaletra had higher CD4 cell counts (median 256 cells/mm3 versus 158 cells/mm3), a lower viral load (10,000 copies/ml versus 100,000 copies/ml) and higher total cholesterol 193mg/dl versus 176mg/dl) than patients who were naïve to protease inhibitors when they started Kaletra.
Treatment with Kaletra did not result in any significant increases in glucose levels in either the protease inhibitor-naïve or -experienced patients at three and six months. However, the investigators found that there was a significant increase in triglyceride levels from baseline at months three (p=0.01) and six (p=0.016), with 70% of patients having a plasma triglyceride level higher than baseline level at month six.
When the investigators analysed these data further, they found that patients who were protease inhibitor-experienced had higher triglycerides at month three (median 221mg/dl versus 191mg/dl, p=0.02) and month six (213mg/dl versus 178mg/dl, p=0.03) than protease inhibitor-naïve individuals, even though both groups had comparable baseline levels (p=0.4). Furthermore, patients with protease inhibitor experience were more likely to have a triglyceride measurement over the clinically significant 400mg/dl level at month three (p=0.001).
The investigators found that total cholesterol levels increased from baseline at month three and month six for both protease inhibitor-experienced and -naïve individuals. The magnitude of the increase for the two groups was comparable (p=0.4). However, only patients with prior protease inhibitor treatment were at risk of experiencing an increase in their total cholesterol level to above the clinically significant 240mg/dl level at month three (p=0.002) and month six (p=0.02).
Levels of HDL cholesterol increased significantly across the entire study population at both three and six months (p=0.01), but the proportion of patients with HDL cholesterol above 40mg/dl at three and six months was not significantly above baseline.
When the investigators looked at the risk factors for elevated lipids, they found that the only significant factor for a glucose level above 126mg/dl after six months of Kaletra was a glucose level of at least this value at baseline. A total of 5.6% of patients had a glucose level of at least this level at month six.
Risk factors for triglycerides above 400mg/dl after six months of Kaletra were triglycerides of at least this level at baseline (p
After six months of Kaletra, 27.8% of patients had total cholesterol above 240mg/dl. Independent risk factors for this were a total cholesterol level of at least this value at baseline (p
The overwhelming majority of patients (78.5%) had depressed levels of HDL (“good”) cholesterol, with men (p=0.04) and individuals using lipid-lowering drugs at baseline (p=0.02) at risk of low HDL cholesterol.
The investigators note that the levels of lipid abnormalities found in their study were “much lower than those reported in lopinavir-ritonavir clinical trials, particularly those involving patients with previous protease inhibitor experience”.
They add that their findings suggest that it is non-drug-related issues, particularly genetic factors, which increase a patient’s risk of developing high blood lipids on Kaletra. They do, however, express concern that lipid-lowering drugs do not appear to be an effective treatment for hyperlipidaemia in individuals taking Kaletra, as taking lipid-lowering therapy at baseline was a risk factor for elevated blood lipids after several months of Kaletra therapy.
Further information on this website
Lopinavir - overview
Body fat and metabolic changes on treatment - menu
Lipodystrophy - factsheets
Martinez E et al. Risk of metabolic abnormalities in patients infected with HIV receiving antiretroviral therapy that contains lopinavir-ritonavir. Clinical Infectious Diseases 38 (on-line edition), 2004.