Patrick G. Clay

Efficacy and Safety of Crofelemer for Noninfectious Diarrhea in HIV-Seropositive Individuals (ADVENT Trial): A Randomized, Double-Blind, Placebo-Controlled, Two-Stage Study

Abstract Background: HIV-associated diarrhea remains a significant concern with limited treatment options. Objective: To determine the optimal dose, efficacy, and safety of crofelemer for noninfectious diarrhea. Methods: This randomized, double-blind, phase 3 trial used a 2-stage design. Both stages included 2-week screening, 4-week placebo-controlled treatment, and 20-week placebo-free (open-label) extension phases. In stage I, 196 HIV-seropositive patients with chronic diarrhea were randomized to crofelemer 125 mg, 250 mg, or 500 mg or placebo twice daily. Using a prospective analysis, the 125-mg twice-daily dose was selected for stage II. In stage II, 180 new patients were randomized to crofelemer 125 mg twice daily or placebo for 4 weeks. Primary efficacy analysis was the percentage of patients (stages I/II combined) who achieved clinical response (defined as ≤2 watery stools/week during ≥2 of 4 weeks). During the placebo-free extension phase, response (≤2 watery stools) was assessed weekly. Results: Significantly more patients receiving crofelemer 125 mg achieved clinical response versus placebo (17.6% vs 8.0%; one-sided, P = .01). Crofelemer 125 mg resulted in a greater change from baseline in number of daily watery bowel movements (P = .04) and daily stool consistency score (P = .02) versus placebo. During the placebo-free extension phase, percentages of weekly responders ranged from 40% to 56% at weeks 11 to 24. Crofelemer was minimally absorbed, well tolerated, did not negatively impact clinical immune parameters, and had a safety profile comparable to placebo. Conclusions: In HIV-seropositive patients taking stable antiretroviral therapy, crofelemer provided significant improvement in diarrhea with a favorable safety profile.

Noninfectious Diarrhea in HIV Seropositive Individuals: a Review of Prevalence Rates, Etiology, and Management in the Era of Combination Antiretroviral Therapy

IntroductionDiarrhea poses a substantial burden for patients with human immunodeficiency virus (HIV), negatively impacting quality-of-life (QoL) and adherence to antiretroviral therapy. During the combination antiretroviral therapy (cART) era, as incidence of opportunistic infection as a cause of diarrhea decreased, incidence of noninfectious diarrhea (including diarrhea as an adverse event [AE] of cART and HIV enteropathy) increased proportionately. A literature search was conducted for information on prevalence, etiology, and treatment options for noninfectious diarrhea in patients with HIV.ResultsFor marketed antiretroviral therapies, up to 28% of patients live with >4 loose or watery stools per day. The US Food and Drug Administration (FDA) does not require pharmaceutical manufacturers to include, within approved prescribing information, prevalence rates for all grades of diarrhea. Traditionally, noninfectious diarrhea management focused on avoiding use of diarrhea-associated cART; symptom management (nonpharmacologic and/or pharmacologic); and, as a last resort, changing cART. Examining the evidence upon which this approach is based reveals that most strategies rely upon anecdotal information and case reports. This review summarizes the literature and updates clinicians on the most recent options for management of noninfectious diarrhea in patients with HIV.ConclusionDiarrhea in patients with HIV is a significant unmet clinical need that contributes to worsening QoL and complicates medical management. Approaching management using a stepwise method of nonpharmacologic (diet), nonprescription (over-the-counter) and, finally, prescription agent changes (modification of cART or addition of an evidence-based antidiarrheal) appears reasonable, despite a lack of clear scientific evidence to support the initial two steps of this approach. If diet modifications, including psyllium and fiber introduction, fail to resolve noninfectious diarrhea in patients with HIV, loperamide followed by crofelemer should be considered. Clinicians are encouraged to review the most recent literature, not rely upon prescribing information. Continued vigilance by HIV providers to the presence of gastrointestinal AEs, even in patients taking the most recently approved antiretroviral agents, is warranted. Additional research is justified in identifying the etiology and management of HIV-associated diarrhea in patients on successful cART regimens.

Medication Regimen Complexity Indices: A tool to focus MTM efforts?

Therefore, where pharmacists are considering targeting interventions when initiating clinical services or a relationship with an HIV clinic, the pMRCI may be a better tool than the ARCI. Researchers next need to establish validity in a prospective fashion and acknowledge there are still some shortcomings of this tool. Using tools such as MCRI may be a mechanism pharmacists can use to facilitate referrals for MTM services. For instance, pharmacists may offer physicians’ practices the services of their pharmacy intern (potentially as part of Introductory and Advanced Pharmacy Practice Experiences) to work within their offices, complete this tool, and provide them with a ranked list of their patients by MRCI score. As all data stay within the physician practice as a quality improvement activity, simply giving the intern access and space to conduct this activity may generate new opportunities for pharmacists and ultimately better outcomes for patients.

Pharmacists enable older patients to “Age Out Loud”?

The Science Updates column highlights research published in journals other than JAPhA that is of interest to the Journals readership. APhA members who have published research are encouraged to forward the PubMed citation, or an electronic version of their article, as soon as they appear or ahead of print, to Contributing Editor Patrick G. Clay, PharmD, AAHIVP, CPI, FCCP at pclay@aphanet.org. May 2017 is when the Administration for Community Living celebrates Older AmericansMonth.1The themeselected this year is “Age Out Loud,” encouraging and facilitating means by which older persons can “stay engaged, strive for wellness, and explore new things.”1 Pharmacists echo these initiatives while recognizing the needs of this very special population. Recent publications demonstrate that pharmacists have made great strides in ways closely alignedwith the 2017 themes. All 3 themes were addressed in a recently published study whereby elderly patients identified as high risk during transition to the community were actively “handed off” to a local community pharmacist who in turn was compensated to provide medication management.2 Patients primarily came to the community pharmacy to have medications reconciled and drug therapy problems identified and addressed with an emphasis on efficacy, adverse events, and adherence. Following a 2-year implementation period, the Pharm2Pharm approach was compared with nonparticipating hospitals, and a clear benefit was seen in the “experimental” arm. Measures revealing benefit included significantly fewer medication-related readmissions (P 1⁄4 0.01; from 72 to 46 per quarter, or a 36.5% reduction), which projected to 394 avoided hospitalizations. Economic modeling revealed that this projected to

Pharmacist impact on patient activation—a key to success

6.6 million dollars in savings at a cost of

Pharmacists entering “a brave new world”

1.3 million dollars or a return on investment of 264%. Also addressing all themes was a focused home-based comprehensive medication review in 25 seniors using grocery storeebased pharmacies.3 With

“Pitching” pharmacists as improvers of transition-of-care outcomes

The Science Updates column highlights research published in journals other than JAPhA that is of interest to the Journals readership. APhA members who have published research are encouraged to forward the PubMed citation, or an electronic version of their article, as soon as they appear or ahead of print, to Contributing Editor Patrick G. Clay, PharmD, AAHIVP, CPI, FCCP at pclay@aphanet.org. Hypertension, smoking, and patient engagement in their own care are all long-standing challenges to address in patients that present overlapping and distinct barriers. As is clear from the existing literature, sole reliance on primary care physicians and office-based approaches to improve these outcomes fail to achieve desired goals.1-3 As an engaged and highly qualified member of the health care teamdregardless of the acceptance of this fact in your own practice environmentdhelp your colleagues to realize the impact that formally utilizing pharmacists can have on patient activation, the key to successful outcomes. Hypertension, despite highly effective therapies, stubbornly remains uncontrolled in more than 80 million adults in the United States, or about 50% of those with the diagnosis.1 Well described key contributing factors of lack of medication optimization, ownership of outcomes by patients, and health literacy were sought to be addressed through a “non-physician” empowerment study. “Non-physician” in this case was a pharmacist. Targeting patients with 3 consecutive blood pressure readings above goal at primary care offices, physicians solicited these patients to engage with their pharmacist who would assess root causes for the lack of control and make changes accordingly. The primary tool used for blood pressure change was an ambulatory blood pressure monitor that connected to the patient’s smart phone. The 156 patients enrolled were compared with a matched cohort of 400 patients who only received care in the primary care offices, and results were compared after 90 days. Control was obtained in 71% of patients in the pharmacist engagement arm compared

Turning the criticism into construction

“Consistency is contrary to nature.”1 Aldous Huxleys premise holds true in medicine like few other fields. Recently, a health policy report published in a leading medical journal provided a wellbalanced overview of the expanding role for community-based “retail clinics.”2 (Use of “retail” instead of “pharmacybased” reminds pharmacists how much further we have to go.) The manuscript gives a generally favorable perspective on the provision of care for “10 simple medical conditions.” Positively, the authors noted that not only were quality and patient satisfaction notably above 90%, but also 61% of retail clinic location patients engaged were without a dedicated primary care provider. It alludes to how these clinics could serve as a novel portal to larger health care systems capable of managing complex conditions for patients who have fallen out of care. The legitimate concern for impact on continuity of care was tempered by an intriguing divergence of “continuity” into “relational” and “informational.” “Relational continuity” focuses on the therapeutics. “Informational continuity” reflects the medical provider currently seeing the patient having access to and using data captured by all of that patients health care providers when making decisions. The authors even hypothesize that with advancements in electronic medical record keeping, when the patient presents to the “traditional” care facility, these community-based,

Pharmacists make oncology and transplant patients happier

The Science Updates column highlights research published in journals other than JAPhA that is of interest to the Journals readership. APhA members who have published research are encouraged to forward the PubMed citation, or an electronic version of their article, as soon as they appear or ahead of print, to Contributing Editor Patrick G. Clay, PharmD, AAHIVP, CPI, FCCP, at pclay@aphanet.org. A notable trend in the medical literature is the focus on approaches to achieve improvements in transitionsof-care. Complementing the increase in publications seeking this are manuscripts describing the role pharmacistsd inpatient and outpatientdin meeting that need. It is notable that pharmacists have demonstrated clear benefit in numerous aspects of transition of care, including at the point of admission,1 preparing the patient for discharge,2 and moving to and from transition-ofcare units.3 Human immunodeficiency virus (HIV) patients represent complicated scenarios to hospitals both from a medication perspective and because of the critical balance achieved with virologic suppression, tolerability, and remaining antiretroviral agents remaining for the patient to use. Maintaining the regimen carefully constructed in the outpatient setting is of utmost importance when HIV patients are admitted to the hospital. A group of researchers in Oklahoma examined how having a pharmacist review medications at admission affected medication errors. The analyses revealed statistically significant improvements (decreases) in medication error rates categorized as incorrect dose (P <0.001), incorrect frequency (P 1⁄4 0.002), and drug interactions (P <0.001) in 330 admissions of 184 patients. Collectively, the pharmacist engagement resulted in a 73.9% reduction of errors (P <0.001) that was independent from antiretroviral regimen, renal function, or any patient demographic. This initiative clearly

Community pharmacists as diabetic complication preventers

The Science Updates column highlights research published in journals other than JAPhA that is of interest to the Journals readership. APhA members who have published research are encouraged to forward the PubMed citation, or an electronic version of their article, as soon as they appear or ahead of print, to Contributing Editor Patrick G. Clay, PharmD, AAHIVP, CPI, FCCP at pclay@aphanet.org. “By perseverance, the snail reached the ark.”