1 Internal Medicine Service and 7 Biochemistry Service, La Paz Hospital, Autónoma University School of Medicine; 2 HIV Unit, Hospital 12 de Octubre, Complutense University School of Medicine; 3 Hospital de Móstoles; 4 Servicio de Enfermedades Infecciosas, Hospital Ramón y Cajal, Alcalá University School of Medicine; 5 Internal Medicine Service, Hospital Príncipe de Asturias, Alcalá University School of Medicine; 6 Servicio de Enfermedades Infecciosas, Hospital Gregorio Marañón, Complutense University School of Medicine, Madrid, Spain
Received 14 November 2004; returned 30 December 2004; revised 12 January 2005; accepted 18 January 2005
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Abstract |
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Methods: A prospective cohort of 107 antiretroviral-naive HIV-infected patients was followed for 12 months after starting lopinavir/ritonavir-based highly active antiretroviral therapy.
Results: At 12 months, percentages of patients with hypercholesterolaemia and hypertriglyceridaemia were 17.4% and 40%, respectively. Mean increases in total cholesterol and triglycerides were 40.7 and 73.3 mg/dL. There was a significant increase in both low-density and high-density (HDL) cholesterol, and no increase in the total cholesterol/HDL ratio (from 4.16 at baseline to 4.49 after 12 months). Baseline cholesterol > 200 mg/dL and triglycerides > 150 mg/dL were independent risk factors for dyslipidaemia, while hepatitis C coinfection appeared to be protective.
Conclusions: Patients with elevated lipid values at baseline have the greatest risk of developing hypercholesterolaemia and hypertriglyceridaemia after starting lopinavir/ritonavir. Antiretroviral-naive patients coinfected with hepatitis C have a low risk of developing hyperlipidaemia after starting lopinavir/ritonavir.
Keywords: antiretroviral therapy , hypercholesterolaemia , hypertriglyceridaemia , cholesterol , triglycerides , high-density cholesterol , low-density cholesterol
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Introduction |
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In the present study, we evaluated lipid changes associated with lopinavir/ritonavir-based highly active antiretroviral therapy (HAART) in HIV-positive patients without previous antiretroviral treatment. In addition, we sought to identify risk factors for lopinavir/ritonavir-associated dyslipidaemia.
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Patients and methods |
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Patients remained on the study as long as lopinavir/ritonavir therapy was not discontinued. For patients who discontinued lopinavir/ritonavir therapy before the end of the study, data were censored at the last visit.
Laboratory parameters were measured at each participating site. Serum samples were drawn in the morning after 12 h of fasting. Total cholesterol, high-density cholesterol (HDL) and triglyceride levels were measured enzymically in serum. Low-density cholesterol (LDL) was calculated using the Friedwald formula or directly measured by ultracentrifugation of lipoproteins if the triglyceride level was > 350 mg/dL. Cholesterol fractions were measured only in centres in which this determination was carried out routinely.
Hypercholesterolaemia and hypertriglyceridaemia were defined according to cut-off values recommended in the US National Cholesterol Education Program guidelines.3
A cut-off value for the total cholesterol:HDL ratio was chosen as 6.5 to define a group at high risk of coronary heart disease.4
Statistical analysis
Comparisons of quantitative variables at each time point were performed using repeated-measures analysis of variance and the Wilcoxon signed rank test. For the comparison of qualitative variables, the McNemar test was used. The time from the start of lopinavir/ritonavir to development of hyperlipidaemia was analysed with the use of the KaplanMeier method and Cox proportional hazards models. A multivariate Cox proportional hazards model was constructed with age, sex, baseline lipid levels, baseline CD4 cell count, use of stavudine, hepatitis C coinfection status and viral load < 400 copies/mL as predictive variables.
A two-tailed P value < 0.05 was considered significant and 95% confidence intervals (CIs) are provided when relevant. All statistical analyses were performed with the use of the SPSS package for Windows v.10.0.
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Results |
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KaplanMeier analyses showed that the probabilities of developing hypercholesterolaemia and hypertriglyceridaemia after 12 months of treatment were 0.24 and 0.68, respectively. Total cholesterol > 200 mg/dL and triglyceride > 150 mg/dL at baseline were associated with the risk of hypercholesterolaemia and hypertriglyceridaemia: the hazard ratios were 3.9 (95% CI 1.410.6; P=0.008) and 3 (95% CI 1.37; P=0.008), respectively. Patients infected with hepatitis C at baseline were significantly less likely to develop hypercholesterolaemia (hazard ratio 0.1; 95% CI 0.010.8; P=0.027) (Figure 1c) and hypertriglyceridaemia (hazard ratio 0.4; 95% CI 0.160.98; P=0.046). Concomitant stavudine therapy appeared to be inversely correlated with the risk of hypertriglyceridaemia but not with the risk of hypercholesterolaemia. The relative hazard ratio for hypertriglyceridaemia in patients treated with stavudine was 0.1 (95% CI 0.20.95; P=0.038).
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Discussion |
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We have found that patients with increased baseline levels of serum cholesterol and triglycerides had the highest risk of developing clinically significant hypercholesterolaemia and hypertriglyceridaemia. Since absolute increases in total cholesterol and triglycerides were similar regardless of baseline levels, this finding probably only means that patients with baseline lipid levels near the upper limit of normal are more likely to exceed it. In mainly antiretroviral-experienced patients,5,6 two groups have found that both high baseline serum cholesterol and triglycerides were strong predictors of development of hypercholesterolaemia and hypertriglyceridaemia.
There is little information about the impact of lopinavir/ritonavir-based HAART on cholesterol lipid fractions. In healthy volunteers, 4 weeks of treatment with lopinavir/ritonavir did not produce changes in LDL or HDL.7 Interestingly, in our study, lopinavir/ritonavir increased significantly both the LDL and HDL. As a consequence, the total cholesterol:HDL ratio did not change significantly. These results are in agreement with those reported by Gathe et al.8
Patients coinfected with hepatitis C had a significantly lower risk of developing hyperlipidaemia (specially hypercholesterolaemia). The lower risk of hyperlipidaemia persisted after adjusting for having an undetectable HIV viral load after 12 months of therapy, suggesting that lower adherence to HAART in coinfected patients was not a confounding factor. Other cohorts have also reported an apparent protective effect of hepatitis C in the development of hypercholesterolaemia after starting antiretroviral treatment.9,10 The mechanism underlying the protective effect of hepatitis C in the risk of developing hyperlipidaemia is not known.
In our study, treatment with stavudine was negatively correlated with the risk of developing hypertriglyceridaemia. This finding is surprising since stavudine has been shown to have an increased risk of hypertriglyceridaemia in a clinical trial that compared stavudine versus tenofovir (both in combination with lamivudine and efavirenz) in antiretroviral-naive patients.11 Compared with the patients reported by Staszewski et al.,11 patients included in our cohort were clearly more advanced. It is possible that the short-term impact of stavudine on lipid values might be different in very advanced HIV-infected patients such as those included in our study. In addition, it is possible that the net effect of stavudine on lipid values might vary depending on the other drugs used in the antiretroviral regimen.
In summary, our study shows that patients with high baseline serum cholesterol and triglycerides have the greatest risk of developing dyslipidaemia after starting lopinavir/ritonavir, while patients with normal baseline lipid values and hepatitis C coinfection have only a modest risk. In antiretroviral-naive patients with advanced HIV infection, lopinavir/ritonavir increased triglycerides and LDL, and also HDL. As a consequence, the total cholesterol:HDL ratios did not change significantly.
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Acknowledgements |
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References |
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2
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3
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4
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Kinosain, B., Glick, H. & Garland, G. (1994). Cholesterol and coronary heart disease: prediciting risks by levels and ratios. Annals of Internal Medicine 121, 6417.
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