Clay, Patrick G.


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Background: Diarrhea remains a significant burden in some HIV+ individuals. Crofelemer is a first-in-class, minimally absorbed, botanically derived drug indicated for symptomatic relief of noninfectious diarrhea in adults with HIV/AIDS taking antiretroviral therapy. This analysis examined the efficacy of crofelemer 125 mg BID in specific subpopulations. Methods: In a 4-week, phase 3, randomized, double-blind, placebo-controlled trial in HIV+ adults receiving antiretroviral therapy, crofelemer 125 mg BID (n = 136) was compared with placebo (n = 138) for reducing noninfectious diarrhea. The primary efficacy endpoint (≤2 watery stools/wk for ≥2 of 4 weeks) was examined in subgroups that differed according to demographic (sex, age, race, time since HIV diagnosis, and duration of diarrhea) and baseline characteristics (severity of diarrhea, prior antidiarrheal medication [ADM] use, stool consistency, viral load, CD4+ cell count, and use of protease inhibitors). Results: At baseline, patients experienced (range of means) 18.9-21.0 watery stools/week, and investigators attributed diarrhea most commonly (75%) to antiretroviral therapy (ritonavir-containing agents, 34%-36%; efavirenz/tenofovir/emtricitabine, 15%-22%) or HIV enteropathy (24%). Across all subgroups considered, treatment effects favored crofelemer. Pronounced treatment differences (crofelemer – placebo) were observed for patients with prior use of ≥2 ADMs (+28%; P 2 watery stools/day (+10%; P = 0.03), diarrhea duration [greater than] 2 years (+11%; P = 0.03), and use of protease inhibitors (+11%; P = 0.021). Conclusions: These findings suggest that the crofelemer antidiarrheal effect is robust and generalizable across patient subpopulations. Purpose (a): To determine which patients with HIV/AIDS are most likely to respond to treatment with crofelemer 125 mg twice daily. Methods (b): Patients and Study Design: HIV+ adults taking a stable ART regimen for ≥4 weeks, with a history of diarrhea (persistently loose stools despite regular antidiarrheal medication use or ≥1 watery bowel movement per day without regular antidiarrheal medication use for ≥1 month). Exclusion criteria included CD4+ cell count/μL and positive gastrointestinal biopsy, culture, or stool test for infectious agents in the previous 4 months. Randomized, double-blind, phase 3 trial of crofelemer 125 mg or placebo administered twice daily for 4 weeks. Assessments: Primary efficacy measure: percentage of patients achieving clinical response, defined as ≤2 watery stools per week for ≥2 of 4 weeks of treatment. Assessment of efficacy was based on patient diaries, which recorded symptoms of diarrhea (eg, stool consistency, stool frequency), adherence to study drug and ART, and use of antidiarrheal and prohibited medications; results were entered daily using an interactive voice response system. Stool consistency score was computed using the mean of all reported stool scores for 1 day; stools were scored using a scale ranging from 1 to 5 (1 = very hard; 5 = watery). Statistical Analyses: Efficacy was assessed in the intention-to-treat population composed of all randomized patients receiving ≥1 dose of study drug (1-sided for primary efficacy analysis, based on technique described by Posch et al13; 2-sided for subgroup analyses). Fisher’s exact test was used for comparisons between crofelemer and placebo for subgroup analyzed. Subgroup analyses were not corrected for multiple comparisons. Results (c): Patient Population: Demographic and baseline characteristics were similar between the 2 groups. Patients in the crofelemer and placebo treatment arms were of similar age (mean, 45 vs 44.8 y), sex (male, 84.6% vs 84.1%), and race/ethnicity (white, 39.0% vs 42.0%; black, 37.5% vs 38.4%; Hispanic, 22.8% vs 18.1%; American Indian/Alaskan Native, 0.7% vs 0%; other, 0% vs 1.5%). Patients in both groups averaged >18.9 watery bowel movements per week. Historical use of antidiarrheal medication was common, reported by 79 patients (58%) receiving crofelemer 125 mg and 83 patients (60%) receiving placebo. Loperamide-containing agents were historically used by 53 (39%) and 60 (43%) patients treated with crofelemer and placebo, respectively. Although not permitted during the 4 weeks of treatment, concomitant use of antidiarrheal medications (eg, loperamide, diphenoxylate /atropine, bismuth subsalicylate) were reported by 1.1% and 4.0% of patients receiving crofelemer or placebo, respectively. Efficacy: A significantly greater percentage of patients achieved clinical response during treatment with crofelemer 125 mg twice daily versus placebo (P = 0.0096; Figure 2). Conclusions (d): Subgroup analyses confirm crofelemer 125 mg twice daily provides robust clinical response across multiple patient subpopulations. Crofelemer was particularly effective in patients with factors associated with severe diarrhea, consistent with its antisecretory effects on intestinal chloride channels.