E. Kelly Hester

Current Options in the Management of Olanzapine-Associated Weight Gain:

OBJECTIVE: To evaluate options for the management of weight gain associated with olanzapine therapy. DATA SOURCES: MEDLINE (1966–May 2004), International Pharmaceutical Abstracts (1970–August 2003), The Cochrane Library, and EMBASE (1974–August 2003) databases were searched using the key words antipsychotics, atypical antipsychotics, olanzapine, and weight gain. Bibliographies of cited articles were reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated and all information deemed relevant was included for this review. DATA SYNTHESIS: Weight gain is a common adverse effect of olanzapine, a member of the atypical antipsychotic class. Data are limited supporting a specific therapeutic approach to the management of weight gain with olanzapine treatment. Reversal of weight gain with lifestyle modifications and adjunctive pharmacologic therapies such as nizatidine and amantadine has been modest. Experience with adjunctive pharmacologic treatment has been limited to small, observational studies and case reports. Although data are limited, weight reduction has been observed in select patients switching from olanzapine to an alternative atypical antipsychotic. CONCLUSIONS: At this time, targeting lifestyle modifications provides the most reasonable approach to minimize weight gain observed with olanzapine therapy. Preliminary evidence evaluating adjunctive pharmacologic treatment for this indication has demonstrated minimal clinical benefit. Switching to an alternative atypical antipsychotic agent associated with less significant weight gain may be appropriate in select patients. Further clinical trials are needed to support a specific therapeutic approach to managing weight gain with olanzapine.

Potential interaction between warfarin and high dietary protein intake.

A 55‐year‐old Caucasian man was receiving warfarin therapy after undergoing aortic valve replacement. His international normalized ratio (INR) was stabilized with warfarin 95 mg/week for 5 weeks. Commencement of a low‐carbohydrate, high‐protein diet resulted in a series of subtherapeutic INRs that led to a 16% increase in the dosage requirement to maintain therapeutic INRs. After the patient discontinued the diet, his INR increased, and several dosage reductions were required until his INR stabilized with his original dosage of 95 mg/week. Two additional case reports have described a possible interaction between warfarin and a high‐protein diet. The potential for increased dietary protein intake to raise serum albumin levels and/or cytochrome P450 activity has been postulated as mechanisms for the resulting decrease in INRs. Given the available animal and human data that demonstrate alterations in drug metabolism in the presence of altered dietary protein intake, an increase in warfarin metabolism due to cytochrome P450 activation appears to be the most likely cause. In addition to the previously reported cases, this case indicates a potential interaction between warfarin and a high‐protein diet. Because of the popularity of high‐protein diets and because of the risks associated with inadequate or excessive warfarin anticoagulation, patients and health care providers should be aware of this interaction to ensure appropriate monitoring when warranted.

Fosamprenavir: Drug Development for Adherence

Objective: To review the pharmacology, pharmacokinetics, virology, safety, efficacy, and clinical use of fosamprenavir. Data Sources: A MEDLINE (1966–July 2005) search was conducted using fosamprenavir, Lexiva, amprenavir, and GW433908 as key words. Abstracts from infectious diseases and HIV scientific meetings were identified. Bibliographies of cited articles were reviewed. Study Selection and Data Extraction: All publications, meeting abstracts, and unpublished information were reviewed and relevant items included. Information from in vitro, preclinical, and Phase II and III clinical trials was included. Data Synthesis: Fosamprenavir is a protease inhibitor (PI) prodrug used for the treatment of HIV-1 infection. The active moiety, amprenavir, is extensively metabolized by CYP3A4. In clinical trials, fosamprenavir was at least as effective as amprenavir, with a reduced pill burden. Fosamprenavir was developed with the intention of reducing the pill burden associated with amprenavir. It has demonstrated comparable safety and efficacy with comparator Pls and is associated with limited cross-resistance to other Pls. Conclusions: Fosamprenavir is a promising antiretroviral agent with favorable efficacy and tolerability. At this time, data indicate the utility of fosamprenavir in treatment-naïve and PI-experienced HIV-infected patients.

Adherence among Rural HIV-Infected Patients in the Deep South: A Comparison between Single-Tablet and Multi-Tablet Once-Daily Regimens

Background: Once-daily (QD), combination antiretroviral therapy (ART) can impact the willingness and ability of patients to take medications as directed. The impact of antiretroviral (ARV) drug adherence influenced by single-tablet (STR) versus multi-tablet regimens (MTR) among patients enrolled in the AIDS Drug Assistance Program (ADAP) in a rural environment has not yet been assessed. Material and Methods: A retrospective chart review evaluated adherence and outcomes in adult HIV-infected patients enrolled in the ADAP at 2 ambulatory clinics in the Southeast, taking either a QD STR (efavirenz [EFV]/emtricitabine/tenofovir [TDF]) or a QD protease inhibitor (PI)-based, MTR (atazanavir [ATV], ritonavir [RTV], and emtricitabine/TDF) by evaluating pharmacy refill records, patient self-reported adherence, and virologic response. Results: A total of 389 patient records were analyzed (STR, n = 165 versus MTR, n = 224). There were more males, a higher percentage of treatment-naive patients, and more patients with a baseline CD4 count of >200 cells/mm3 in the MTR group. Based on refill records, more patients on MTR were >90% adherent (61.6% versus 51.5%, P = .047). In a multivariable analysis, being treatment experienced was a negative predictor (odds ratio [OR] = 0.48, 0.29-0.78) for adherence. Regimen choice was not associated with adherence. More patients taking MTR were virologically suppressed at the end of the observation period. Regardless of the regimen, being >90% adherent was a significant predictor of virologic suppression (OR = 3.51, 1.98-6.23). Conclusion: Treatment-experienced patients enrolled in ADAP are less likely to be adherent. A QD PI-based MTR may result in comparable adherence to an STR in a rural HIV-infected population.

Development and Validation of a Rubric to Evaluate Diabetes SOAP Note Writing in APPE

Objective. To develop and establish validity for a grading rubric to evaluate diabetes subjective, objective, assessment, plan (SOAP) note writing on primary care (PC) advanced pharmacy practice experiences (APPEs), and to assess reliability and student perceptions of the rubric. Methods. Ten PC APPE faculty members collaborated to develop a rubric to provide formative and summative feedback on three written SOAP notes per APPE student over a 10-month period. Correlation analyses were conducted between rubric scores and three criterion variables to assess criterion-related validity: APPE grades, Pharmaceutical Care Ability Profile Scores, and Global Impression Scores. Inter-rater and intra-rater reliability testing were completed using Cohen’s kappa and Intraclass Correlation Coefficients (ICC). Student perceptions were assessed through an anonymous student survey. Results. Fifty-one students and 167 SOAP notes were evaluated using the final rubric. The mean score significantly increased from the first to second SOAP note and from the first to third SOAP note. Statistically significant positive correlations were found between final rubric scores and criterion variables. The ICC for inter-rater reliability was fair (.59) for final rubric scores and excellent for intra-rater reliability (.98 to1.00). Students responded that the rubric improved their ability (84.9%) and confidence (92.4%) to write SOAP notes. Conclusion. The rubric may be used to make valid decisions about students’ SOAP note writing ability and may increase their confidence in this area. The use of the rubric allows for greater reliability among multiple graders, supporting grading consistency.

The Rise and Fall of Efavirenz

Since its introduction to market in 1998, efavirenz (EFV) has been a cornerstone in highly active antiretroviral treatment regimens and the benchmark for clinical trials evaluating new agents in treatment-naive patients. It was incorporated as a component of the first ‘‘one pill, once daily’’ treatment regimen for HIV infection, Atripla (EFV/ emtricitabine/tenofovir [TDF]) (a trademark of BristolMyers Squibb Company, Princeton, NJ, USA). Although EFV was considered a first-line HIV treatment option for many years, the most recent update to the Department of Health and Human Services (DHHS) guidelines in April 2015 was historic as it is now considered an alternative agent. In contrast, other guidelines have defined different roles for EFV, with the World Health Organization (WHO) guidelines recommending Atripla as the sole preferred agent for all treatment-naive patients and the guidelines from the Grupo de Estudio de SIDA (GeSIDA) making similar recommendations to the DHHS. Although the DHHS and GeSIDA guidelines have taken a stance by lowering the recommendation for EFV on the spectrum of antiretroviral therapy, it opens up discussion for several important clinical practice questions—is there a patient or patient population best suited for an EFV-based regimen relative to the other regimens? Should clinicians change patients currently stable on EFV-based regimens to one of the preferred regimens? This opinion paper reviews these questions. Despite EFV being relegated to alternative status, it possesses several advantageous characteristics and remains the drug of choice in the nonnucleoside reverse transcriptase inhibitor (NNRTI) class. For example, similar to other NNRTIs, EFV displays a long terminal half-life. This pharmacokinetic benefit resulted in studies demonstrating ‘‘forgiveness’’ in regard to suboptimal adherence and creating the possibility of ‘‘drug holidays’’ for certain patient populations. Efavirenz first gained notoriety among prescribers when it was successfully compared to indinavir (IDV) and later formulated as part of a single-tablet regimen, leading to an accrual of clinical experience. Virologically, the findings of the AIDS Clinical Trials Group 5142 study reinforced the potency of EFV when compared to protease inhibitor (PI)-based regimens. Additionally, simplification studies with EFV-based single-tablet regimens in patients controlled on multitablet regimens indicated durability of virologic suppression and improved adherence. Finally, EFV distributes effectively into the cerebrospinal fluid, achieving therapeutic concentrations that could confer additional benefit. The importance of central nervous system (CNS) penetration of antiretroviral therapy continues to be debated, given that this is a sanctuary site for replication, and perhaps evidence will continue to mount suggesting this should be given higher consideration when selecting a regimen. Despite its clear efficacy in the management of HIV infection, it does have a number of important adverse effects that may limit its use. Although recently debated, EFV remains pregnancy category D, which precludes its use in females of childbearing age. Furthermore, it is fraught with drug–drug interactions due to its inductive and/or inhibitory effects on CYP450 enzymes, thus often complicating other medical management. Despite the possibility of drug holidays in some patients, EFV does have a low-genetic barrier to resistance and poses a concern for patients who struggle with consistent medication adherence. Moreover, transmitted resistance is particularly important for EFV as the K103N mutation, which confers high-level resistance to EFV and other firstgeneration NNRTIs, is most likely to be transmitted in newly acquired infections. Conversely, PIs and dolutegravir have a higher genetic barrier and are far less likely to display baseline resistance in treatment-naive patients and should be considered in patients who have a history of noncompliance.