SAFETY AND TOLERABILITY OF CROFELEMER 125 MG TWICE DAILY IN THE TREATMENT OF NONINFECTIOUS DIARRHEA IN HIV-SEROPOSITIVE PATIENTS ON ANTIRETROVIRAL THERAPY: RESULTS FROM A PHASE 3, 48-WEEK OPEN-LABEL STUDY

Diarrhea remains a substantial health concern in patients with HIV in the era of combination antiretroviral therapy (ART), despite the decline in opportunistic infectious diarrhea. For example, noninfectious diarrhea attributable to ART-related adverse events (AEs) has a reported prevalence in the community of up to 28% of patients with HIV who are receiving ART. Diarrhea in patients with HIV is commonly a leaky-flux or secretory diarrhea, which is characterized by increased secretion of chloride ions (Cl-) and subsequent sodium and water flow into the gastrointestinal lumen. Crofelemer (Fulyzaq™, Salix Pharmaceuticals, Inc., Raleigh, NC, USA) is a minimally absorbed, first-in-class, botanically derived drug indicated for the symptomatic relief of noninfectious diarrhea in adults with HIV. Following oral dosing of crofelemer, plasma concentrations of the drug were below the level of quantification in [greater than] 99% of patients with HIV and diarrhea. Crofelemer is a dual inhibitor of the cyclic adenosine monophosphate (cAMP)-stimulated cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel and the calcium-activated Cl- channel (CACC). In a phase 3, double-blind, placebo-controlled trial (ADVENT), crofelemer 125 mg twice daily significantly reduced diarrhea in patients with HIV receiving ART compared with placebo, and the safety profile was comparable to placebo for up to 24 weeks. Purpose (a): To evaluate the long-term (up to 48 weeks) safety and tolerability of crofelemer 125 mg twice daily for the treatment of noninfectious diarrhea in patients with HIV. Methods (b): Phase 3, multicenter, open-label study of crofelemer 125 mg twice daily for up to 48 weeks. Results (c): Overall, 189 patients (75.6%) experienced ≥1 AE during this open-label study; the majority of AEs (90.5% of patients) were mild or moderate in intensity. The most commonly reported AEs were infection-related (eg, upper respiratory tract [16.8%], intestinal parasitic [12.4%], Giardia [8.0%]; none drug-related) or gastrointestinal-related (eg, nausea [5.6%], constipation [5.6%]) –Most patients (10 of 14 [71.4%]) reporting a constipation AE also used ADMs during the study. Only 9 (3.6%) patients reported diarrhea as an AE •AEs considered at least possibly related to study drug occurred in 9.2% of patients; the most commonly reported were constipation (3.6%), abdominal distension (2.0%), abdominal pain (1.2%), and flatulence (1.2%). No deaths occurred during the study; serious AEs occurred in 20 patients (8.0%), including infection in 10 patients; none were considered drug-related. Conclusions (d): Crofelemer 125 mg twice daily was well tolerated with a low incidence of AEs in HIV-seropositive patients with noninfectious diarrhea receiving ART, which is consistent with the minimal absorption of crofelemer. In this study, minimal clinical deterioration of immune status was observed for up to 48 weeks, suggestive of adherence to ART regimens and continued ART efficacy.