Effects of atazanavir/ritonavir or fosamprenavir/ritonavir on the pharmacokinetics of rosuvastatin.

BACKGROUND: Rosuvastatin (RSV) is a potent statin with a lower potential for drug interactions. However, recent data have revealed unexpected increases in RSV concentrations with lopinavir/ritonavir. The objective is to study the pharmacokinetic interaction of RSV with atazanavir/ritonavir (ATV/RTV) or fosamprenavir/ritonavir (FPV/RTV). METHODS: In a prospective pharmacokinetic drug interaction study, six HIV-seronegative, healthy adult volunteers received single 10-mg doses of RSV at baseline and after 6 days of ATV/RTV and FPV/RTV, with 6-day washout periods. Plasma concentrations of RSV and its metabolites, N-desmethyl-RSV and RSV-lactone, were measured by using a internally validated tandem mass spectrometric (LC-MS/MS) method over 24 hours. RESULTS: Compared to baseline, the area under the plasma concentration-time curve (AUC 0-24h) and maximum plasma concentration (Cmax) of RSV increased by 213% and 600%, respectively, and the time to reach Cmax was shorter (1.75 h vs. 2.91 h) when given with ATV/RTV (P < 0.05). However, coadministration with FPV/RTV did not significantly affect the pharmacokinetics of RSV. The AUC 0-24h of N-desmethyl-RSV was not significantly affected by either combinations, but that of RSV-lactone increased (P < 0.05) by 61% and 76% after coadministration with ATV/RTV and FPV/RTV, respectively. CONCLUSION: ATV/RTV significantly increases the plasma concentrations of rosuvastatin, most likely by increasing rosuvastatin's oral bioavailability. Dose limitations of RSV with ATV/RTV may be needed.

Safety and efficacy of simvastatin for the treatment of dyslipidemia in human immunodeficiency virus-infected patients receiving efavirenz-based highly active antiretroviral therapy.

STUDY OBJECTIVES: To evaluate the safety and efficacy of simvastatin for treatment of dyslipidemia in patients with the human immunodeficiency virus (HIV) who were receiving efavirenz-based highly active antiretroviral therapy (HAART), and to evaluate the effect of simvastatin when added to efavirenz on CD4(+) count, HIV viral load, and frequency of attainment of patient-specific National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III lipid goals. DESIGN: Retrospective medical record review. SETTING: Veterans Affairs health care system in Dallas, Texas. PATIENTS: Thirteen HIV-infected men who received a stable efavirenz-based HAART regimen concurrently with simvastatin 20 mg/day, and 19 HIV negative men who received simvastatin 20 mg/day (controls). MEASUREMENTS AND MAIN RESULTS: Demographic, clinical, and laboratory data were collected before and after starting simvastatin. Reductions in lipid profile values in the HIV-infected group versus HIV-negative group were as follows: total cholesterol -20% versus -28% (p=0.15), low-density lipoprotein cholesterol (LDL) -36% versus -41% (p=0.06), non-high-density lipoprotein cholesterol (non-HDL) -22% versus -33% (p=0.212), and total cholesterol:HDL ratio -33% versus -30% (p=0.26). These effects were seen without any documented adverse drug reactions or changes in viral and immunologic control. However, 28% fewer HIV-infected patients were able to achieve NCEP ATP III LDL goals compared with HIV-negative subjects. CONCLUSION: These preliminary comparative data suggest that simvastatin can be safely and effectively used to treat dyslipidemia in HIV-infected patients receiving efavirenz-based HAART without compromising viral or immunologic control. However, our results are suggestive of slight lessening of the LDL-lowering effects, which might be explained by the known reduction in simvastatin levels with efavirenz. Furthermore, fewer HIV-infected patients were able to meet their NCEP ATP III goals compared with HIV-negative controls, highlighting the difficulty in treating this population to current standards of care.

A multimodal, evidence-based approach to achieve lipid targets in the treatment of antiretroviral-associated dyslipidemia: case report and review of the literature.

Metabolic abnormalities associated with the treatment of human immunodeficiency virus (HIV) infection are well-recognized problems that increase cardiovascular risk. As a result of the complexity of treating both HIV- and antiretroviral-related comorbidities, strategies that improve adverse drug events while maintaining viral control are in critical need. Although guidelines have somewhat helped in the general approach and in first-line strategies for managing dyslipidemia in patients receiving antiretrovirals, a paucity of data exist to guide clinicians in treating patients whose conditions are refractory to first-line options or who are at substantial risk for cardiovascular events. Further complicating the choice of lipid-lowering strategy is the lack of randomized controlled data from the HIV-affected population and a concern about clinically significant drug-drug interactions. We describe an HIV-infected patient with efavirenz-associated dyslipidemia at very high cardiovascular risk who had not achieved his primary or secondary lipid goals despite 2 years of treatment in a lipid specialty clinic. Lipid control was accomplished in 10 weeks with a targeted, stepwise approach of switching efavirenz to nevirapine, followed by rosuvastatin 20 mg/day, which was sustained for at least 10 months. Of most importance, this outcome was achieved without any clinically significant alteration in virologic or immunologic control. This case report highlights the potential for a pharmacist-guided, multistep approach that addresses HIV-related dyslipidemia and incorporates the pharmacokinetic literature to guide lipid-lowering therapy and promote the attainment of goals based on current standards of care.

Multicenter evaluation of vancomycin dosing: emphasis on obesity.

BACKGROUND: There is a paucity of data available regarding the dosing of antimicrobials in obesity. However, data are available demonstrating that vancomycin should be dosed on the basis of actual body weight. METHODS: This study was conducted at 2 tertiary care medical centers that did not have pharmacy-guided vancomycin dosing programs or other institutional vancomycin dosing policies or protocols. Patients who received vancomycin between July 1, 2003, and June 30, 2006, were stratified by body mass index and randomly selected from the computer-generated queries. Patients >or=18 years of age with a creatinine clearance of at least 60 mL/min who received vancomycin for at least 36 hours were included. RESULTS: Data were collected on a random sampling of 421 patients, stratified by body mass index, who met the inclusion criteria. Most patients in each body mass index category received a fixed dose of vancomycin 2 g daily divided into 2 doses (underweight 82%, normal weight 90%, overweight 86%, and obese 91%). Adequate initial dosing (>or=10 mg/kg/dose) was achieved for 100% of underweight, 99% of normal weight, 93.9% of overweight, and 27.7% of obese patients (P < .0001). Ninety-seven percent of underweight, 46% of normal weight, 1% of overweight, and 0.6% of obese patients received >or=15 mg/kg/dose recommended by several Infectious Diseases Society of America guidelines. Pharmacists also failed to correct inadequate dosing because only 3.3% of patients receiving less than 10 mg/kg/dose had their regimen changed in the first 24 hours of therapy. CONCLUSION: In this multicenter pilot study, obese patients routinely received inadequate empiric vancomycin using a lenient assessment of dosing. Greater efforts should be undertaken to ensure patients receive weight-based dosing because inadequate dosing can lead to subtherapeutic concentrations and potentially worse clinical outcomes.

Lipid-lowering efficacy and safety after switching to atazanavir-ritonavir-based highly active antiretroviral therapy in patients with human immunodeficiency virus.

STUDY OBJECTIVE: To evaluate the efficacy, safety, and lipid-lowering effects after switching from a non-atazanavir-containing, protease inhibitor-based highly active antiretroviral therapy (HAART) to atazanavir-ritonavir-based HAART in patients infected with human immunodeficiency virus (HIV). DESIGN: Multicenter, noncontrolled, retrospective study. SETTING: Three tertiary teaching hospitals. PATIENTS: Thirty-six patients with HIV infection, aged 18 years or older, who were receiving non-atazanavir-containing, protease inhibitor-based HAART that was switched to atazanavir 300 mg-ritonavir 100 mg-based HAART without changes in nucleoside reverse transcriptase inhibitors and confounders known to alter serum lipid levels. MEASUREMENTS AND MAIN RESULTS: Lipid profiles measured 4 weeks-6 months before the switch, as well as follow-up lipid profiles measured 4 weeks-6 months after receiving the new HAART regimen, were evaluated. The switch resulted in the following changes in lipid levels: total cholesterol -9% (p=0.002), low-density lipoprotein cholesterol -13% (p<0.001), high-density lipoprotein cholesterol (HDL) -2% (p=0.431), triglycerides -23% (p=0.007), non-HDL -11% (p=0.002), total cholesterol:HDL ratio -10% (p=0.004), and triglyceride:HDL ratio -24% (p=0.019). A subgroup analysis was conducted on the lipid profiles of nine patients who still met the strict inclusion and exclusion criteria up to 9 months after the switch; it showed that the reductions in their lipid profiles were sustained. In addition, 33% more patients achieved their National Cholesterol Education Panel (NCEP) Adult Treatment Panel (ATP) III cholesterol goals. No significant changes were noted in median (interquartile range) CD4+ counts (372 [236-551] and 361 [217-464] cells/mm(3), p=0.118) or in number of patients with undetectable HIV viral loads ([defined as < 50 copies/ml] 32/36 and 31/36 patients, p>0.05) between baseline and after the switch, respectively. CONCLUSION: Switching to an atazanavir-ritonavir-based HAART regimen was associated with significant improvement in lipid profiles, similar to those seen in clinical trials, without compromising safety or viral and immunologic control. In addition, more patients were able to achieve their NCEP ATP III goals.

A retrospective study of the lipid-lowering efficacy and safety of ezetimibe added to hydroxy methylglutaryl coenzyme A reductase therapy in HIV-infected patients with hyperlipidemia.

BACKGROUND: Abnormalities in lipid metabolism are a well-described consequence of human immunodeficiency virus (HIV) infection being treated with highly active antiretroviral therapies (HAART). OBJECTIVE: The purpose of this study is to evaluate the lipid-lowering efficacy and safety of ezetimibe added to existing hydroxy methylglutaryl coenzyme A reductase (statin) therapy in HIV-infected patients with hyperlipidemia. METHODS: This is a retrospective study utilizing a comprehensive electronic patient registry to identify all adult HIV-infected patients seen at the Dallas Veterans Affairs (VA) Medical Center during a 4-year period from October 1, 2002 through October 1, 2006. RESULTS: A total of 26 HIV-infected patients initiated on ezetimibe 10 mg were identified, with 14 adult males meeting strict criteria for inclusion. Median age was 54 years (interquartile range [IQR], 45-59) with a median duration of HIV of 13 years, CD4 count of 513 cells/mm(3) (IQR, 289-736), and 9 of 14 patients had undetectable viral loads at baseline. Initiation of ezetimibe 10 mg resulted in a significant decrease in total cholesterol (TC) from baseline (-12.9%, P = 0.001); low-density lipoprotein cholesterol (LDL-C; -25.7%, P = 0.001); and non-high-density lipoprotein cholesterol (non-HDL-C; -23.9%, P = 0.001). There was also a nonsignificant decrease in triglycerides (15.8%, P = 0.43), and an increase in number of patients achieving National Cholesterol Education Program/Adult Treatment Panel III goal for LDL-C after initiation of ezetimibe (+20.9%, P = 0.125). These improvements occurred without adverse effects or changes in virologic and immunologic control. CONCLUSION: Addition of ezetimibe to existing statin therapy in HIV-infected VA patients treated with HAART significantly reduces TC, LDL-C, and non-HDL-C concentrations without apparent side effects or compromising of virologic control.