CROFELEMER FOR HIV-ASSOCIATED DIARRHEA: SUSTAINED EFFICACY, SAFETY, AND ADHERENCE DURING A 6-MONTH RANDOMIZED, PLACEBO-CONTROLLED TRIAL

Combination antiretroviral therapy (cART) in HIV+ individuals has increased life expectancy; however, increased ART exposure is also associated with adverse effects that can negatively impact overall health, work productivity, and healthcare resource utilization. Diarrhea, an adverse event (AE) of ART, remains a substantial burden associated with reduced quality of life and may result in ART nonadherence or treatment failure. Reported prevalence of diarrhea in the community is up to 28% of patients receiving cART. Crofelemer, extracted from the stem bark latex of the Croton lechleri tree, is a minimally absorbed, first-in-class antidiarrheal agent indicated for the symptomatic relief of noninfectious diarrhea in adults with HIV/AIDS receiving ART. Crofelemer inhibits chloride ion (Cl–) secretion and accompanying high-volume water loss in secretory diarrhea via dual inhibition of cystic fibrosis transmembrane conductance regulator and calcium-activated Cl– channels in the intestinal epithelium. Purpose (a): To assess patient adherence to and efficacy and safety of crofelemer 125 mg twice daily for up to 6 months. Methods (b): Randomized, phase 3, double-blind, placebo-controlled, 2-stage trial (Figure 1). The optimal crofelemer (Fulyzaq™, Salix Pharmaceuticals, Inc., Raleigh, NC, USA) dose (125, 250, or 500 mg twice daily) was determined in stage 1. Based on the stage 1 interim efficacy and safety analysis, crofelemer 125 mg twice daily was selected as the optimal dose and was evaluated in additional patients in stage 2; data for crofelemer 125 mg twice daily were combined (stage 1 and 2). Primary efficacy measure: percentage of patients achieving clinical response, defined as ≤2 watery stools per week for ≥2 of 4 weeks during the placebo-controlled phase (1-sided analysis). Results (c): Demographic and baseline characteristics were similar between crofelemer 125 mg twice daily (n = 136) and placebo (n = 138) groups (Table 1); patients had a mean of 2.7 to 3.0 watery stools per day (ie, >18 watery stools per week). Primary measure: A significantly larger percentage of patients treated with crofelemer achieved clinical response compared with placebo (17.6% vs 8.0%; P < 0.01). Continued and sustained improvement in weekly clinical response and a mean improvement from baseline in diarrhea symptoms was observed in patients who continued to receive crofelemer 125 mg twice daily during the placebo-free phase. Conclusions (d): Crofelemer 125 mg twice daily was efficacious and well tolerated, and improvements in noninfectious diarrhea symptoms appeared to be durable for at least 6 months in an HIV+ population receiving stable cART. Treatment of diarrhea in HIV+ individuals may provide several important benefits, such as improvement in cART adherence.