Lana Gerzenshtein

Low incidence of renal impairment observed in tenofovir-treated patients

OBJECTIVES To compare the incidence of renal impairment in HIV-infected patients exposed versus unexposed to tenofovir and to characterize risk factors associated with renal impairment. METHODS We undertook a retrospective cohort and nested case-control study of 514 Northwestern University HIV Outpatient Study participants who received antiretroviral therapy (ART) between 1 August 2001 and 31 July 2007. Renal impairment was defined as meeting at least one of two validated criteria based on serum creatinine, calculated glomerular filtration rate and creatinine clearance. Multivariable analysis was performed to identify risk factors for renal impairment. RESULTS Renal impairment occurred in 14% (n = 72) of the cohort and was not correlated with exposure to tenofovir in univariate analyses. In multivariable analysis, more advanced age [odds ratio (OR) = 1.04, P = 0.02], diabetes (OR = 3.6, P < 0.01), decreased weight (OR = 0.97, P = 0.02) and endpoint CD4 ≤200 cells/mm(3) (OR = 2.5, P = 0.03) were positive predictors of renal impairment; tenofovir exposure (OR = 0.41, P = 0.01) was negatively correlated with renal impairment. CONCLUSIONS Tenofovir-containing ART was associated with less renal impairment than ART without tenofovir in a patient cohort with a high incidence of renal impairment. Chronic co-morbid conditions known to be associated with renal impairment should be excluded prior to attributing renal impairment to tenofovir.

Breakthrough Candida Infections in Patients Receiving Voriconazole

OBJECTIVE To describe 2 instances of breakthrough Candida infection in 2 patients on treatment doses of voriconazole. CASE SUMMARIES A 27-year-old woman with systemic lupus erythematosus was receiving high-dose voriconazole (400 mg twice daily) for central nervous system lesions of unknown origin and developed oral thrush. The patient was receiving concomitant therapy with phenytoin 400 mg/day. The voriconazole dose was increased to 400 mg 3 times daily, and the thrush resolved. A 50-year-old man with HIV infection was receiving enfuvirtide, lamivudine, tenofovir, and efavirenz 600 mg/day, as well as prophylactic trimethoprim/sulfamethoxazole and azithromycin. He was started on voriconazole 200 mg twice daily for pulmonary aspergillosis and developed esophageal candidiasis. The voriconazole dose was increased to 350 mg twice daily, and the thrush eventually resolved. DISCUSSION Both reactions were probable according to the Naranjo probability scale. Significant drug interactions may have played a role in the development of breakthrough infections in these patients, specifically with phenytoin and efavirenz. Voriconazole is metabolized primarily by CYP2C19, as well as CYP2C9 and CYP3A4. Voriconazole is also known to inhibit these enzymes, and the manufacturer reports an extensive list of drugs that interact with voriconazole. CONCLUSIONS Although requiring systematic evaluation, there may be a role for voriconazole serum concentration monitoring to ensure therapeutic efficacy when significant drug interactions are suspected.

Antimicrobial drug-induced thrombocytopenia: a review of the literature.

The incidence of drug-induced thrombocytopenia (DIT) is not well-defined, but is estimated to occur at a minimum of 10 cases per million per year. This review will focus on the potential DIT associated with specific antibacterial, antifungal, antiviral, and antiparasitic agents. Case reports, cohort studies, and clinical trials were identified using PubMed search terms for each antimicrobial along with the Boolean combiner AND to match with the following outcomes: thrombocytopenia and bleed. Thrombocytopenia was defined as a platelet count of < 100 × 10(9)/L or a decrease in platelet count of at least 50% from baseline. A majority of the data supporting antimicrobial-induced thrombocytopenia consist of case reports and small studies. However, clinicians should be vigilant in monitoring patient platelet counts, as an immune-mediated mechanism is frequently responsible for this hematologic adverse effect and is therefore unpredictable.

Clinical implications of antiretroviral drug interactions with warfarin: a case–control study

OBJECTIVES Warfarin, a frequently prescribed anticoagulant with a narrow therapeutic index, is susceptible to drug-drug interactions with antiretroviral therapy (ART). This study compared the warfarin maintenance dose (WMD) between patients receiving and not receiving ART and evaluated predictors of warfarin dosage among those on ART. METHODS This was a case-control (1:2) study. Cases were HIV-infected patients receiving warfarin and protease inhibitor (PI)- and/or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART. Controls were randomly selected HIV-uninfected patients receiving warfarin. The WMD was compared between cases and controls and between cases on varying ART regimens. Bivariate comparisons were performed and a linear regression model was developed to identify predictors of WMD. RESULTS We identified 18 case and 36 control patients eligible for inclusion. Cases were younger than controls (mean age: 45.8 versus 63.1 years, P < 0.01), more often male (72.2% versus 36.1%, P=0.02) and more likely to be African American (50.0% versus 22.2%, P=0.04). ART was classified as PI-based (n=9), NNRTI-based (n=7) and PI + NNRTI-based (n=2). The WMD (mean ± SD) differed between cases and controls (8.6  ±  3.4 mg versus 5.1 ± 1.5 mg, P < 0.01), but not ART regimens (PI: 8.8  ±  4.5 mg; NNRTI: 8.6   ± 1.8 mg; PI + NNRTI: 7.3  ±  3.3 mg; P = 0.86). Race and ritonavir dose were independent predictors of WMD, predicting an increase of 3.9 mg (95% CI: 0.88-6.98, P = 0.02) if a patient was African American or 3.7 mg (95% CI: 0.53-6.89, P = 0.03) if the total daily ritonavir dose was 200 mg. CONCLUSIONS The required WMD was significantly higher in patients receiving ART. Prompt dose titration to achieve a higher WMD with vigilant monitoring may be required due to these drug-drug interactions.

Integration of outpatient infectious diseases clinic pharmacy services and specialty pharmacy services for patients with HIV infection

PURPOSE The integration of specialty pharmacy services and existing outpatient clinical pharmacy services within an infectious diseases (ID) clinic to optimize the care of patients with human immunodeficiency virus (HIV) infection is described. SUMMARY The management of HIV-infected patients is a highly specialized area of practice, often requiring use of complex medication regimens for reduction of HIV-associated morbidity and mortality prophylaxis and treatment of opportunistic infections, and prevention of HIV transmission. To maximize the effectiveness and safety of treatment with antiretroviral agents and associated pharmacotherapies, an interdisciplinary team is often involved in patient care. At Chicago-based Northwestern Medicine (NM), the outpatient ID clinic has long worked with an interdisciplinary care team including physicians, clinical pharmacists, nurses, and social workers to care for patients with HIV infection. In April 2014, specialty pharmacy services for patients with HIV infection were added to the NM ID clinics care model to help maintain continuity of care and enhance patient follow-up. The care model includes well-defined roles for clinical pharmacists, pharmacy residents and students on rotation, and licensed pharmacy technicians. Specialty pharmacy services, including medication education, prescription fulfillment, assistance with medication access (e.g., navigation of financial assistance programs, completion of prior-authorization requests), and treatment monitoring, allow for closed-loop medication management of the HIV-infected patient population. CONCLUSION Integration of specialty pharmacy services with the interdisciplinary care provided in the outpatient NM ID clinic has enhanced continuity of care for patients with HIV infection in terms of prescription filling, medication counseling, and adherence monitoring.

Dosing Nucleoside Reverse Transcriptase Inhibitors in Adults Receiving Continuous Veno-Venous Hemofiltration

Background and ObjectiveCharacteristics of nucleoside reverse transcriptase inhibitors (NRTIs) make the drug class susceptible to elimination via continuous veno-venous hemofiltration (CVVH), potentially leading to suboptimal drug concentrations if given at the recommended anephric doses during CVVH. The objective of this study was to formulate NRTI dosing recommendations for adults receiving CVVH.MethodsA mathematical formula that estimates the amount of drug likely to be removed during CVVH at various flow rates was used to calculate the supplemental NRTI dose required during CVVH.ResultsA proposed table of dosing recommendations for NRTIs during CVVH is presented.ConclusionClinicians should utilize these recommendations in the context of each individual patient, taking into consideration patient-specific factors and severity of illness. Future pharmacokinetic research correlating plasma and intracellular concentrations of NRTIs during CVVH is warranted to elucidate appropriate dosing.

Evaluation of nucleoside reverse transcriptase inhibitor dosing during continuous veno-venous hemofiltration

Background Unpredictable drug concentrations may lead to suboptimal exposure to nucleoside reverse transcriptase inhibitors (NRTIs) due to inadequate doses administered during continuous veno-venous hemofiltration (CVVH), which in turn may lead to decreased antiretroviral efficacy and possibly further HIV disease progression. Objective To compare administered doses of NRTIs to calculated doses of NRTIs to evaluate if patients were expected to have a favorable pharmacokinetic exposure profile while receiving CVVH. Methods The NRTI dose was compared to a table of recommendations based on a mathematical formula that estimates the amount of drug expected to be removed during CVVH. Results Twelve patients were on 27 NRTIs. Eleven (41%) NRTI doses were expected to provide a favorable pharmacokinetic profile based on pharmacokinetic mathematical calculations. Conclusion The majority of NRTIs were potentially not optimally dosed based on proposed pharmacokinetic calculations.