Author(s): Poorvi Chordia 1 , Rodger D MacArthur [*] 2
chloride channels; crofelemer; HIV; secretory diarrhea
Secretory diarrhea is a global health concern and is a major cause of mortality and morbidity. This condition can result from viruses (such as rotavirus), bacterial toxins (such as cholera and enterotoxogenic Escherichia coli [ETEC]), reduced absorptive surface area from disease or intestinal resection, secretagogues (such as bile acids, drugs like antiretroviral therapy [ART] and laxatives, hormones and poisons) or medical problems that compromise intestinal function  . ETEC and cholera are the most common cause of secretory diarrhea worldwide with devastating effects and high case fatality rates  .
Diarrhea secondary to gastrointestinal opportunistic infections was a common problem in individuals with AIDS, typically seen when the CD4+ cell count decreased to less than 200 cells/mm3  . With the introduction of ART, the prevalence of gastrointestinal opportunistic infections has decreased  . However, non-infectious diarrhea continues to be a common problem in HIV-infected individuals and can cause a significant impairment in quality of life. The exact prevalence of diarrhea in the era of ART is unclear due to variations in defining HIV-associated diarrhea (e.g., definition, assessment tools and duration). However, HIV-infected persons are more likely to report diarrhea than non-infected individuals  . In a study by Siddiqui et al ., 163 HIV-infected persons (92% on ART, median CD4 count 370 cells/mm 3 ) were compared with 253 seronegative controls. The prevalence of diarrhea was four-times greater in HIV-infected individuals than seronegative individuals (28.2 vs 7.1%, odds ratio [OR]: 6.65; 95% CI: 3.36-13.17), with significantly worse scores on health-related quality of life (HRQOL) surveys  . On comparison of HRQOL between HIV-infected persons with diarrhea and HIV-infected persons without diarrhea, the HIV-infected persons with diarrhea scored significantly worse than those without diarrhea in 9 out of 11 domains of the HRQOL. In a survey on HIV-associated diarrhea, 40% individuals indicated that diarrhea negatively impacted quality of life. In addition to restricting schedules and staying closer to home, diarrheal symptoms were emotionally distressing and associated with feelings of shame and humiliation  .
Non-infectious diarrhea in HIV-infected persons is usually secretory in nature and caused by either ART, HIV-associated enteropathy or HIV-associated malignancies and pancreatitis  . ART are the most common cause of non-infectious diarrhea, and although all classes of ART can contribute to diarrhea, it is particularly seen with ritonavir-boosted protease inhibitor (PI) regimens  .
Treatment of non-infectious diarrhea in HIV-infected individuals with HIV has been anecdotal and primarily supportive  . Commercially available anti-diarrheal agents lack targeted activity against the etiology of diarrhea and are only minimally effective. Therefore, treatment of non-infectious diarrhea in persons with HIV has been an unmet clinical need. Crofelemer, a novel anti-diarrheal agent, recently approved by the US FDA may help bridge this gap. It is a plant extract derived from the latex of the Croton lechleri tree found in South America. Crofelemer inhibits the intestinal luminal chloride channels, reducing the electrical gradient that drives the efflux of sodium and water into the gastrointestinal lumen. This in...