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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.

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.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. Patientsor=18 years of age with a creatinine clearance of at least 60 mL/min who received vancomycin for at least 36 hours were included.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 receivedor=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.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.

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).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.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 (P0.05). 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 (P0.05) by 61% and 76% after coadministration with ATV/RTV and FPV/RTV, respectively.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.

The objective of present research is to evaluate the lipid lowering efficacy and safety of switching within non-nucleoside reverse transcriptase inhibitors (NNRTI) in HIV-infected patients. This is a multicenter, retrospective study utilizing a comprehensive electronic patient registry to identify all adult HIV-infected patients seen from October 1, 1998 through October 1, 2006, who substituted efavirenz for nevirapine (EFV→NVP) or vice-versa (NVP→EFV), without change in other antiretrovirals. Lipid profiles before and after the switch were analyzed. A total of 124 patients were identified with 14 male (EFV→NVP, n = 9; NVP→EFV, n = 5) patients meeting the strict criteria for inclusion. An EFV→NVP switch resulted in significant reductions in TC -16% and non-HDL -25% (p≤0.02) and a trend towards a reduction in LDL-C -12%, TG -27%, TC/HDL -23%, TG/HDL -48% and an increase in HDL-C +15% without any changes to BMI, viral or immunological control. However, a NVP→EFV switch appeared to result in a non-significant worsening of LDL-C +29%, HDL-C -8%, TG +36%, non-HDL +28%, TC/HDL +57% and TG/HDL +46%. Lastly, more patients achieved their lipid goals when switched from EFV to NVP. These data suggest that switching from EFV to NVP-based HAART is associated with lipid improvement, however, switching from NVP to EFV-based HAART is associated with worsening of serum lipids.

Background Treatment of human immunodeficiency virus (HIV) with protease inhibitors (PIs) is associated with insulin resistance, triglyceride-rich dyslipidemia, and fat redistribution. Atazanavir (ATV), a potent once-daily PI, has been recognized for its convenience to patients, and some studies describe improved lipid metabolism. However, its effects on insulin sensitivity have not been elucidated. We conducted this study to test the hypothesis that ATV improves insulin resistance and dyslipidemia. Methods We prospectively studied 9 HIV-infected men with dyslipidemia (median age, 53 years; baseline triglyceride level, >200 mg/dL) on stable PI-containing antiretroviral therapy who elected to change PI therapy to ritonavir-boosted ATV therapy, dose of 300/100 mg. We measured insulin resistance at baseline and after 12 weeks of therapy using a hyperinsulinemic euglycemic clamp (insulin dose, 200 mU/m2 minute). Fasting lipid profiles and body composition (whole-body dual energy x-ray absorptiometry) were also measured at baseline and after 12 weeks. Results All 9 patients completed the study and maintained undetectable viral loads (Conclusions Using the gold-standard euglycemic clamp, ritonavir-boosted ATV therapy improved PI-induced insulin resistance among dyslipidemic HIV-infected men on PI-based antiretroviral therapy. These findings were not attributable to a change in body weight and provide further evidence for ATV's unique metabolic profile among the PIs.

Pravastatin has generally been considered a safe and effective option for HIV-infected patients on highly active antiretroviral therapy (HAART). However, pravastatin concentrations are known to significantly decrease with concomitant efavirenz (EFV) use. Currently there are no studies determining if these reductions in pravastatin possibly translate into an attenuation of its lipid lowering efficacy when used in HIV-infected patients on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART. To evaluate the differences in the lipid lowering efficacy of pravastatin for the treatment of dyslipidemia in HIV-infected patients on NNRTI-based HAART compared to protease inhibitor (PI)-based regimens. A single center, retrospective evaluation of a comprehensive electronic HIV registry that identified HIV-infected, Veterans Affairs (VA) patients who received pravastatin 20 mg plus NNRTI or PI-based HAART from January 1997 to November 2006 who met the strict criteria for inclusion. A total of 18 patients [NNRTI (n = 7) and PI (n = 11)] met the strict criteria for inclusion. In HIV-infected patients taking NNRTI-based HAART there was a reduction in TC by -10.1%, LDL by -12% and non-HDL by -12.2% within 6 months after starting pravastatin 20 mg. In HIVinfected patients taking PI-based HAART, there was a reduction in TC by -10.1%, in LDL by -21.1% and in non-HDL by -13.8% within 6 months after starting pravastatin 20 mg. In both groups, only one additional patient achieved their patient specific lipid goals. In either group these reductions were seen without any apparent adverse drug events or compromise to virologic or immunologic control. This initial evaluation suggests that pravastatin’s efficacy may be attenuated with NNRTIs versus PI-based HAART, possibly due to known reductions in pravastatin concentrations when administered with NNRTI-based regimens. These effects were seen without any apparent compromises to safety and should be validated in a prospective study.

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.

Uremic bleeding syndrome is a recognized consequence of renal failure and can result in clinically significant sequelae. Although the pathophysiology of the condition has yet to be fully elucidated, it is believed to be multifactorial. This article is a review of both the normal hemostatic and homeostatic mechanisms that operate within the body to prevent unnecessary bleeding, as well as an in-depth discussion of the dysfunctional components that contribute to the complications associated with uremic bleeding syndrome. As a result of the multifactorial nature of this syndrome, prevention and treatment options can include one or a combination of the following: dialysis, erythropoietin, cryoprecipitate, desmopressin, and conjugated estrogens. Here, these treatment options are compared with regard to their mechanism of action, and onset and duration of efficacy. An extensive review of the clinical trials that have evaluated each treatment is also presented. Lastly, we have created an evidence-based treatment algorithm to help guide clinicians through most clinical scenarios, and answered common questions related to the management of uremic bleeding.

Background Atazanavir (ATV), an HIV protease inhibitor (PI) that may be preferred for the treatment of HIV-infected patients with cardiovascular comorbidities because of its favourable effects on plasma lipids, has been associated with cardiac rhythm disturbances. Objective To quantify the effect of ATV on corrected QT (QTc) and QTc dispersion (QTd), markers of the potential for cardiac dysrhythmia, in patients switching from other PIs to ATV. Methods In this prospective, single-centre, open-label study, 12-lead electrocardiograms were performed for subjects at baseline, 2 h after the first dose of ATV, and 1 month after initiation of ATV. Results Twenty-one patients (19 received ritonavir-boosted ATV) completed the study. There was a trend towards an increase in the QTc at 2 h after the first dose [mean±standard deviation 3.19±8.0 ms; 95% confidence interval (CI) −0.47 to 6.85 ms; P=0.084]. There was no difference between QTc values at baseline and at 1 month (−1.5±8.75 ms; 95% CI −5.50 to 2.46; P=0.43). There was a nonsignificant decrease in the QTd between baseline and 2 h (−5.1±15.19 ms; 95% CI −13.22 to 2.96; P=0.197) and between baseline and 1 month (−0.61±15.04 ms; 95% CI −8.1 to 6.87; P=0.865). A significant increase in the PR interval (7.4±10.7 ms; 95% CI 2.5 to 12.25 ms; P=0.005) was observed at 1 month. Conclusions The use of ATV did not result in increases in the QTc interval or QTd. However, PR interval monitoring may be warranted in patients with underlying heart block or those treated with atrioventricular nodal blocking agents.

The search for NSAIDs with less gastrointestinal toxicity led to the introduction of the selective cyclo-oxygenase-2 (COX-2) inhibitors. However, following their introduction into the market, concerns have developed regarding their safety, particularly their cardiovascular safety. The purpose of this study was to assess the cardiovascular risk (events included were myocardial infarction, stroke and myocardial infarction-related deaths) associated with long-term (180 days of exposure) and short-term (or=180 days of exposure) use of non-selective NSAIDs, including 'preferential COX-2 inhibitors' (i.e. etodolac, nabumetone and salsalate), and selective COX-2 inhibitors.A retrospective analysis of the Veterans Integrated Service Network 17 Veterans Affairs (VA) database was conducted. Medicare data and Texas Department of Health mortality data were incorporated to capture events occurring outside the VA healthcare network. Patientsor=35 years of age who received celecoxib, rofecoxib, ibuprofen, etodolac and naproxen from 1 January 1999 through 31 December 2001, were included. Multivariate Cox proportional hazard models were used to analyse the relationship between cardiovascular risk and NSAID use, including selective COX-2 inhibitor use, while adjusting for various risk factors.We identified 12 188 exposure periods (11 930 persons) and 146 cardiovascular events over the entire study period. Compared with long-term ibuprofen use, long-term use of celecoxib (adjusted hazard ratio [HR] 3.64; 95% CI 1.36, 9.70) and rofecoxib (adjusted HR 6.64; 95% CI 2.17, 20.28) was associated with a significant increase in cardiovascular risk. When restricted to patientsor=65 years of age, the cardiovascular risks associated with long-term celecoxib (adjusted HR 7.36; 95% CI 1.62, 33.48) and rofecoxib (adjusted HR 13.24; 95% CI 2.59, 67.68) use increased. Short-term use of celecoxib (adjusted HR 0.75; 95% CI 0.42, 1.35) and rofecoxib (adjusted HR 0.85; 95% CI 0.39, 1.86) was not associated with any significant change in cardiovascular risk when compared with short-term ibuprofen use. Neither long- nor short-term exposure to naproxen and etodolac was associated with cardionegative or cardioprotective effects when compared with ibuprofen use.The findings of this observational study, along with recent clinical trial results, suggest that prolonged exposure to selective COX-2 inhibitors may be associated with an increased risk of adverse cardiovascular outcomes.

Atazanavir is the first once-daily protease inhibitor for the treatment of human immunodeficiency virus type 1 infection and should be used only in combination therapy, as part of a highly active antiretroviral therapy (HAART) regimen. In addition to being the most potent protease inhibitor in vitro, atazanavir has a distinct cross-resistance profile that does not confer resistance to other protease inhibitors. However, resistance to other protease inhibitors often confers clinically relevant resistance to atazanavir. Currently, atazanavir is not a preferred protease inhibitor for initial HAART regimens. In treatment-naive patients, atazanavir can be given as 400 mg/day. However, atazanavir should be pharmacologically boosted with ritonavir in treatment-experienced patients or when coadministered with either tenofovir or efavirenz. Patients who receive atazanavir experience similar rates of adverse events compared with patients receiving comparator regimens. An exception is an increased risk of asymptomatic hyperbilirubinemia, which is due to competitive inhibition of uridine diphosphate-glucuronosyltransferase 1A1. Although hyperbilirubinemia is a common adverse drug reaction of atazanavir therapy (22-47%), fewer than 2% of patients discontinue atazanavir therapy because of this adverse effect. Common adverse effects reported with atazanavir include infection, nausea, vomiting, diarrhea, abdominal pain, headache, peripheral neuropathy, and rash. Of significance, fewer abnormalities have been observed in plasma lipid profiles in patients treated with atazanavir compared with other protease inhibitor-containing regimens. As with other protease inhibitors, atazanavir is also a substrate and moderate inhibitor of the cytochrome P450 (CYP) system, in particular CYP3A4 and CYP2C9. Clinically significant drug interactions include (but are not limited to) antacids, proton pump inhibitors, histamine type 2 receptor antagonists, tenofovir, diltiazem, irinotecan, simvastatin, lovastatin, St. John's wort, and warfarin. We conclude that atazanavir is a distinctively characteristic protease inhibitor owing to its in vitro potency, once-daily dosing, distinct initial resistance pattern, and infrequent association with metabolic abnormalities.

Unfractionated heparin and warfarin have been the mainstay of treatment of venous thromboembolism (VTE) for approximately half a century. However, both agents are difficult to dose accurately, require frequent blood testing and dosage adjustment, and can cause serious adverse effects. Oral direct thrombin inhibitors may provide more predictable anticoagulation with oral dosing, without the need for frequent blood test monitoring and without the adverse effects seen with conventional agents. The oral direct thrombin inhibitor closest to being marketed is ximelagatran, which has been through phase III trials. Available data thus far suggest that the efficacy and safety of this agent may allow it to replace both heparin (and low-molecular-weight heparin) and warfarin for VTE treatment and long-term prophylaxis. Concerns about ximelagatran that require further study are a 5-9% rate of transient elevation in liver enzyme levels, drug interactions, how patient adherence can be ensured in the absence of blood tests, and whether alterations in renal or hepatic function will require dosage adjustments. Although there is more to learn about ximelagatran, available data suggest that it is likely to be the most significant therapeutic advance in this area in over 50 years.

Serotonin (5-hydroxytryptamine [5-HT])1 receptor agonists, such as those used for treating migraine, can cause coronary artery contraction, coronary spasm, and even myocardial infarction. Tegaserod maleate is a relatively new 5-HT4 receptor agonist with moderate affinity for the 5-HT1 receptor. Currently, it is approved only for treatment of irritable bowel syndrome in women who have constipation as the primary symptom. However, it is also being administered as a promotility agent in patients with gastroparesis. Since tegaserod has affinity for the 5-HT1 receptor, it is plausible that tegaserod could cause the same types of cardiovascular adverse events seen with agents prescribed for management of migraine. We report the first case of a man who experienced a myocardial infarction after receiving only two 6-mg doses of tegaserod; we also provide a hypothesis regarding this event. When considering prescribing a drug with 5-HT1 receptor agonist activity, clinicians should review the patient's medical history specifically for the presence of underlying cardiovascular risk factors.

hildren’s Medical Center, Dallas, TX, USA (Dr. Nguyen); Texas Tech University Health Sciences Center School of harmacy—Dallas/Ft. Worth Regional Campus (Drs. Bain, Hall, and Busti); School of Pharmacy at the Dallas VA edical Center, 4500 S. Lancaster Rd., Dallas, TX 75216, USA (Drs. Bain, Bedimo, Hall, and Busti); and University of exas Southwestern Medical Center, Dallas, TX, USA (Drs. Bain, Bedimo, and Hall)

Human immunodeficiency virus (HIV) and psychiatric disorders frequently occur together and may result in concurrent use of atypical antipsychotic (AAP) agents and highly active antiretroviral therapy (HAART). Both classes of agents have been shown to cause clinically important dyslipidemia and metabolic dysregulation in a population at high baseline cardiovascular risk. The combined effects of concurrent use of these drug classes on lipids and other metabolic indices remain undetermined. This retrospective cohort included HIV(+) or HIV(-) patients at the Dallas Veterans Affairs Medical Center who received either HAART or AAP agents. Subjects were separated into three groups: HAART+AAP, HAART alone, and a control group of HIV(-) patients taking AAP agents. The combined HAART and AAP use on lipid parameters was examined. Included patients received treatment for at least 12 weeks and had baseline and follow-up lipids within 1 year. A total of 107 male patients were analyzed with a mean age of 51 years. Mean time on HAART regimen was 49 months (HAART+AAP; n=27) and 24 months (HAART alone; n=40), and mean time on AAPs was 20 months (HAART+AAP) and 22 months (AAP alone; n=40). The addition of an AAP agent to medication regimens in HIV(+) patients, resulted in trends toward worsening TC, LDL, and non- HDL cholesterol levels, although not statistically significant. Ratios of TC/HDL were insignificant between groups following initiation of HAART alone, AAP alone, or in combination; however a greater TG/HDL ratio was noted in those receiving HAART+AAP relative to HAART or AAP alone.

BACKGROUND Ezetimibe inhibits intestinal absorption of cholesterol. METHODS Multicentered double-blind, randomized, placebo-controlled, crossover study to determine the short-term safety, efficacy, and tolerability of ezetimibe in combination with ongoing statin therapy in HIV-infected adults with elevated low-density lipoprotein cholesterol (LDL-C). Participants on stable HAART with fasting LDL-C at least 130 mg/dl and stable statin were randomized to ezetimibe 10 mg daily or placebo for 12 weeks followed by 4 weeks of washout and then 12 weeks with alternative study assignment. Percentage and absolute change in LDL-C (primary endpoint), total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), apolipoprotein B, and high sensitivity C-reactive protein were compared. Changes in clinical symptoms and safety laboratory measurements were assessed. RESULTS Forty-four participants enrolled: 70% men, median age 49 years, 43% White/Non-Hispanic, median CD4 cell count 547 cells/microl, and 95% HIV RNA less than 50 copies/ml. Median (interquartile range) percentage change in LDL-C was -20.8% (-25.4, -10.7) with ezetimibe and -0.7% (-10.3,18.6) with placebo; the median within-participant effect of ezetimibe was -14.1% (-33.0, -5.0; P < 0.0001). Median difference in absolute LDL-C values between ezetimibe and placebo was -32 mg/dl (-58, -6, P < 0.0001). Significant differences in within-participant effect of ezetimibe were noted for total cholesterol -18.60% (-27.22, -11.67, P < 0.001), non-HDL-C -23.18% (-33.14, -14.36, P < 0.0001), and apolipoprotein B -8.73% (-18.75, 1.99, P = 0.02). No significant changes seen in HDL-C, triglyceride, or high sensitivity C-reactive protein. Ezetimibe was well tolerated. Adverse events were similar between phases. CONCLUSION The present short-term study found adding ezetimibe to ongoing statin therapy was well tolerated and effective in reducing LDL-C, total cholesterol, non-HDL-C, and apolipoprotein B. Adding ezetimibe to statin therapy offers reasonable treatment option for HIV-infected patients with elevated LDL-C.

Background Type 2 diabetes mellitus (T2DM) is a coronary heart disease (CHD) risk equivalent warranting aggressive management of dyslipidemia and tight glycemic control. Recent reports demonstrate a paradoxic decrease in high-density lipoprotein cholesterol (HDL-C) with thiazolidinedione (TZD) and fibrate combination therapy. Objective Evaluate change in HDL-C from start of combination therapy to 1 year and assess the proportion, characteristics, and regimens of patients who developed a ≥20% decrease in HDL-C from baseline. Methods Patients with T2DM treated concurrently with a combination of TZD and fibrate were identified through retrospective query from a Veterans Affairs medical center database. HDL-C was recorded for 1 year after patients started combination therapy. Logistic regression analysis was performed to determine any predictors of HDL-C change. Results A total of 322 patients were included in the analysis. There was no significant differences in mean ± standard deviation HDL-C from baseline to end point (36.8 ± 8.5 to 40.3 ± 11.8 mg/dL; P = 0.097). There was a subset of patients identified (13%; n=43) on combination therapy who experienced a ≥20% reduction in HDL-C. Of these patients, a decrease in HDL-C was more likely to occur with fenofibrate-based regimens (odds ratio 3.08, 95% confidence interval 1.22 to 7.75; P = 0.018). There was a trend toward more of these patients in this subset to have the combination of rosiglitazone and fenofibrate in their profiles (odds ratio 2.82, 95% confidence interval 0.98 to 8.0; P = 0.064). Conclusion Our study demonstrated that a subset of patients with T2DM experienced a paradoxic decrease in HDL-C when taking a fibrate and TZD combination.

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.

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).Multicenter, noncontrolled, retrospective study.Three tertiary teaching hospitals.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.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% (p0.001), 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 as50 copies/ml] 32/36 and 31/36 patients, p0.05) between baseline and after the switch, respectively.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.

The objective of this study was to evaluate the incidence of new onset or worsening congestive heart failure in Veteran's Affairs (VA) patients who have received infliximab, etanercept, or adalimumab, and to compare mortality rates in these patients to control populations. We enrolled three groups of patients for this retrospective study: TNF-alpha group (n = 103), a rheumatoid arthritis (RA) control group (n = 100), and a control group without RA (n = 100). All patients at our VA facility who had received at least one dose of the TNF-alpha antagonists were included in the TNF-alpha group. Admissions for CHF did not differ between the three groups: TNF-alpha 7 (6.7%), RA control 8 (8%), non-RA control 7 (7%); P = 0.940. Mortality rates were not significantly different: TNF-alpha 4 (3.8%), RA control 7 (7%), non-RA control 11 (11%); P = 0.147. Our study showed no difference between the three groups in either CHF exacerbation or mortality.

Patients with various rheumatologic and inflammatory disease states commonly require drugs known to decrease the inflammatory or autoimmune response for adequate control of their condition. Such drugs include nonsteroidal antiinflammatory drugs (NSAIDs), cyclooxygenase (COX)-2 inhibitors, corticosteroids, disease-modifying antirheumatic drugs (DMARDs), and biologic response modifiers. These drugs affect inflammation and local immune responses, which are necessary for proper wound healing in the perioperative setting, thereby potentially resulting in undesirable postoperative complications. Such complications include wound dehiscence, infection, and impaired collagen synthesis. The end result is delayed healing of soft tissue and bone wounds. The current literature provides insight into the effect of some of these drugs on wound healing. For certain drugs, such as methotrexate, trials have been conducted in humans and direct us on what to do during the perioperative period. Whereas with other drugs, we must rely on either small-animal studies or extrapolation of data from human studies that did not specifically look at wound healing. Unfortunately, no clear consensus exists on the need and optimum time for withholding therapy before surgery. Likewise, clinicians are often uncertain of the appropriate time to resume therapy after the procedure. For those drugs with limited or no data in this setting, the use of pharmacokinetic properties and biologic effects of each drug should be considered individually. In some cases, discontinuation of therapy may be required up to 4 weeks before surgery because of the long half-lives of the drugs. In doing so, patients may experience an exacerbation or worsening of disease. Clinicians must carefully evaluate individual patient risk factors, disease severity, and the pharmacokinetics of available therapies when weighing the risks and benefits of discontinuing therapy in the perioperative setting.

Synopsis: Diabetes is recognized as a coronary heart disease (CHD) risk equivalent, warranting aggressive management of dyslipidemia and tight glycemic control. Recently, published case reports and retrospective reviews have shown a paradoxical decrease in HDL-C when TZDs and fibrates are used in combination. Purpose: Evaluate any change in HDL-C from start of combination therapy to one year and assess the proportion, characteristics and regimens of patients who developed a 20% decrease in HDL-C from baseline. Methods: Type 2 diabetic patients treated concurrently with a TZD and fibrate were identified through retrospective query between January 1999 to September 2007. Patients were included if they were 18 years old or above and had a lipid panel six months prior to and within one year after start of combination therapy. Patients were excluded if there were changes in non-study lipid medications, thyroid function or had nephrotic syndrome. Nominal data was analyzed using Fisher’s exact test and Chi-square as appropriate. Interval data was analyzed using ANOVA. A univariate analysis was conducted using a logistic regression model to evaluate predictors (SPSS version 16.0). Results: A total of 965 patients were identified and 322 met the inclusion criteria. The mean SD age was 64 11.3 and the majority of the patients were male (99%). There was no statistically significant difference in mean SD HDL-C from baseline to endpoint (36.8 mg/dL 8.5 to 40.3 mg/ dL 11.8; p 0.097). There was a subset of patients identified (13%; n 43) on combination therapy who experienced a 20% reduction in HDL-C. Of these patients, a decrease in HDL-C was three times more likely to occur with fenofibrate-based regimens (OR 3.08 95% CI 1.22– 7.75; p 0.018). Moreover, patients in this subset were more likely to receive the combination of rosiglitazone and fenofibrate (OR 2.82 95% CI 0.98-8.0; p 0.064), although not statistically significant. Conclusions: Our study demonstrated that there is no difference in HDL from baseline to endpoint in patients taking combination TZD and fibrate therapy. However, there was a subset of patients who experienced a paradoxical decrease in HDL-C. This decrease was more likely to occur in patients who receive fenofibrate-based regimens. Diabetic patients are at increased risk for CHD related complications, which may be further increased in a certain subgroup of patients if placed on combination therapy with fibrates and TZDs. Further studies need to be conducted to determine what characteristics these patients have in common.

Authors’ response to “Tranexamic acid and uremic bleeding: evidence-based treatment recommendations”

To the Editor: As appropriately pointed out in the review article by Izzedine et al1, cyclosporine, tacrolimus, and sirolimus share the same metabolic pathways (CYP450 3A4 isoenzyme) as all of the protease inhibitors (PI) used in treatment of human immunodeficiency virus (HIV). However, Table 1 lacks current information regarding other PIs. Atazanavir sulfate (Reyataz®), FDA approved in June 2003, competitively inhibits CYP3A4, CYP1A2, CYP2C9, uridine diphosphate-glucuronosyl transferase (UGT) 1A1 enzyme, and P-glycoprotein (P-gp) at doses used in current clinical practice2,3. Although no pharmacokinetic studies have been completed with the above immunosuppressants, it would be reasonable to assume that atazanavir would cause increases in their plasma levels.