Lipid changes in HIV-infected patients who started rescue therapy with an amprenavir/ritonavir-based highly active antiretroviral therapy.

Abstract

The use of protease inhibitors (PI) has been related to hyperlipidemia [1,2]. Ritonavir is the PI that has been more frequently related to hypertriglyceridemia. On the other hand, amprenavir seems to have less of an impact on blood lipid levels. Data reported currently show moderate or severe lipid abnormalities (grade 3 or 4) in less than 5% of patients receiving amprenavir, and only in rare cases did they need to discontinue therapy as a result of this adverse event [3–6]. When low doses of ritonavir are co-administered with amprenavir, the total number of daily pills could be reduced and the pharmacokinetics improved, raising its inhibitory quotient, enhancing potency and the likelihood of achieving complete viral suppression in pretreated patients [7]. However, there is currently a lack of information about the impact of this combination on blood lipid levels. To assess the changes in lipid levels in patients who receive amprenavir/ritonavir (600/100 mg every 12 h) in combination with other drugs in the context of a rescue therapy, we collected fasting blood samples from 31 consecutive patients with virological failure who were considered to be candidates to start a new regimen based on amprenavir. Total cholesterol and triglyceride levels, CD4 cell counts and viral loads were measured before beginning the new therapy, 4 and 16 weeks later. The statistical analysis was made using the non-parametric Wilcoxon test for paired samples and the Mann–Whitney test when applicable. Twenty-one out of 31 patients (68%) were men, with a median age of 39 years. Most had been diagnosed with AIDS (57%), and 75% had a CD4 cell count of less than 200 cells. Patients were severely pre-treated (a median of five previous antiretroviral regimens), and received a median of five different drugs in the new treatment: two or three nucleosides in all of them and non-nucleosides in 11 patients (eight efavirenz and three nevirapine). Four patients received dual boosted PI with amprenavir/lopinavir/ritonavir. Baseline viral loads and CD4 cell counts were 18 200 copies/ml [interquartile range (IQR) 3845–38 726] and 210 cells/mm3 (IQR 131–374), and median total cholesterol and triglyceride levels were 185 mg/dl (IQR 162–215) and 147 mg/dl (IQR 89–207), respectively. Thirteen patients had total cholesterol levels greater than 200 mg/dl (maximum 280), and eight patients had triglyceride levels greater than 200 mg/ml (maximum 1380). Only one patient was under lipid-lowering therapy (fenofibrate) at the beginning of the study, and it was discontinued after one month of starting therapy with amprenavir. Therefore, no patients needed any lipid drug to be added to the therapy in all the monitoring time. Sixteen weeks after changing antiretroviral therapy a significant viral load decrease was observed (60% reached < 50 copies/ml) and a CD4 cell count increase (median 52 cells/mm3). There were no increases in total cholesterol and triglyceride levels at weeks 4 and 16 after starting amprenavir/ritonavir when compared with baseline values (median increase in total cholesterol 6 and 5 mg/dl; P = 0.3 and 0.8; and triglyceride levels 22 and 32 mg/dl; P = 0.2 and 0.4, respectively). Nevertheless, those patients with higher total cholesterol levels at baseline (> 200) had a significant decrease in in total cholesterol at week 16 when compared with patients with normal basal total cholesterol levels (median difference 33 mg/dl; P = 0.029). Patients with basal triglyceride levels greater than 200 had a higher decrease in triglyceride levels when compared with patients with normal triglyceride levels at baseline (median difference 82 mg/dl; P = 0.001). It is important to note that the average increase in cholesterol at the fourth month after changing therapy was 3%. This is a very small increase compared with 190% in ritonavir-treated patients, 110% in nelfinavir-treated patients, and 70% in indinavir-treated patients reported from Swiss Cohort Study [8]. Amprenavir is currently one of the best therapy options for patients with several previous treatments and with mutations of resistance in the HIV protease gene. The use of amprenavir boosted with ritonavir enhances its inhibitory quotient, raising the trough level (Cmin) of amprenavir, which is associated with better virological response, even in some viruses with mutations of resistance to other drugs in the same family. Even in the case of HIV with mutations of resistance to amprenavir, it could be possible to overcome this resistance by increasing amprenavir blood levels (inhibitory quotient) boosting it with ritonavir. Lopinavir/ritonavir could have the same advantages, but this drug frequently develops severe dyslipidemia that could limit its use for patients with a family or personal background of lipid or metabolic disorders. In that case, the use of amprenavir/ritonavir could be a good option. Nevertheless randomized studies addressing this subject are needed, to explore the long-term impact of amprenavir/ritonavir therapy on lipid levels.