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  53rd ICAAC Interscience Conference on
Antimicrobial Agents and Chemotherapy
September 10-13, 2013, Denver CO
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Crofelemer Effective for Severe or PI-Related Diarrhea in Placebo Trial
  Crofelemer Effective for Severe or PI-Related Diarrhea in Placebo Trial
53rd ICAAC, September 10-13, 2013, Denver
Mark Mascolini
Crofelemer, a botanically derived agent indicated for symptomatic relief of noninfectious diarrhea in antiretroviral-treated people, proved particularly effective against severe, intransigent diarrhea and protease inhibitor (PI)-related diarrhea in subgroup analyses of a double-blind placebo-controlled trial [1].
Noninfectious diarrhea remains a problem for many HIV-positive people and can lead to reduced quality of life and poor antiretroviral adherence. Research indicates that about one quarter of antiretroviral-treated people suffer from diarrhea [2,3]. Crofelemer, a minimally absorbed, first-in-class antidiarrheal, directly inhibits mechanisms of secretory diarrhea and is licensed to treat noninfectious diarrhea in antiretroviral-treated people at a dose of 125 mg twice daily [4,5].
US researchers conducted this subgroup analysis of a phase 3 placebo-controlled trial of crofelemer in people taking a stable antiretroviral regimen for at least 4 weeks and with (1) persistently loose stools despite regular antidiarrheal medication, or (2) one or more watery bowel movements daily for at least 1 month without antidiarrheal medication. The trial excluded people with a CD4 count below 100 or a biopsy-confirmed infectious cause of diarrhea in the preceding 4 months.
The investigators defined clinical response at two or fewer watery stools per week for at least 2 of the 4 treatment weeks. The intention-to-treat efficacy analysis considered randomized patients who took at least one dose of study drug. Subgroups considered were defined by demographics (gender, age, race, and time since HIV diagnosis) and baseline traits (diarrhea duration, diarrhea severity, prior antidiarrheal medication, stool consistency, viral load, CD4 count, and PI use).
The analysis involved 136 people randomized to crofelemer and 138 randomized to placebo. The crofelemer and placebo groups were similar in age (average 45 and 44.8 years), gender (84.6% and 84.1% men), race (39% and 42% white, 37.5% and 38.4% black), CD4 count (average 497.5 and 530.3), proportion with a viral load below 400 (81.6% and 84.1%), use of ritonavir (33.8% and 35.5%), and daily watery bowel movements (2.7 and 3.0). About 60% in each group had used antidiarrheal drugs. The investigators attributed diarrhea to antiretroviral therapy in 75% of study participants and to HIV infection in 24%.
Overall a significantly higher proportion in the crofelemer arm than the placebo arm achieved study-defined clinical response (17.6% versus 8.0%, P = 0.0096). Clinical response was more likely with crofelemer than with placebo in every subgroup and significantly more likely with crofelemer in several subgroups:
-- Age 48 or younger: 17% versus 7.3%, P= 0.0466
-- Men: 19.1% versus 7.8%, P = 0.0124
-- Whites: 24.5% versus 8.6%, P = 0.0373
-- CD4 count below 404: 18.2% versus 2.6%, P = 0.0233
-- Viral load below 400 copies: 17.7% versus 7.9%, P = 0.0233
-- Diarrhea duration more than 2 years: 18.7% versus 7.6%, P = 0.0299
-- More than 2 watery bowel movements per day: 12.0% versus 2.4%, P = 0.0260
-- Stool consistency score above 4 (more watery): 17.1% versus 8.4%, P = 0.0498
-- Use of other antidiarrheal medication in previous 4 weeks: 14.9% versus 0%, P = 0.0039
-- History of antidiarrheal use: 18.1% versus 3.5%, P = 0.0025
-- Use of protease inhibitor: 17.2% versus 6.2%, P = 0.0212
The researchers noted that several factors associated with more severe diarrhea favored a significantly better clinical response to crofelemer than to placebo. Some groups with a nonsignificant difference in response--such as women and people with a viral load above 400--included few participants. Although the trial prohibited use of other antidiarrheals during the 4-week treatment period, small proportions of participants (1.1% on crofelemer and 4.0% on placebo) used other medications. These low rates, the authors noted, indicate that observed clinical responses can be attributed to crofelemer.
The investigators concluded that crofelemer is "particularly effective in patients with factors associated with severe diarrhea, consistent with its antisecretory effects on intestinal chloride channels."
1. MacArthur RD, Clay PG, Barrett AC, et al. Identifying high responder populations to crofelemer for treatment of noninfectious diarrhea in HIV+ individuals. 53rd ICAAC. September 10-13, 2013. Denver. Abstract H-1264.
2. Call S, Heudebert G, Saag M, Wilcox CM. The changing etiology of chronic diarrhea in HIV-infected patients with CD4 cell counts less than 200 cells/mm3. Am J Gastroenterol. 2000;95:3142-3146.
3. Siddiqui U, Bini EJ, Chandarana K, et al. Prevalence and impact of diarrhea on health-related quality of life in HIV-infected patients in the era of highly active antiretroviral therapy. J Clin Gastroenterol. 2007;41:484-490.
4. Salix Pharmaceuticals. Fulyzag (crofelemer) prescribing information.
5. Frampton JE. Crofelemer: a review of its use in the management of non-infectious diarrhoea in adult patients with HIV/AIDS on antiretroviral therapy. Drugs. 2013;73:1121-1129.