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Good HIV-Related Diarrhea Control With 20 to 24 Weeks of Crofelemer
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9th IAS Conference on HIV Science (IAS 2017), July 23-26, 2017, Paris
Mark Mascolini
Three quarters of HIV-positive people taking crofelemer in an extension of a placebo-controlled trial had at least a 50% drop in diarrhea, and half had complete resolution [1]. These outcomes exceed those recorded in the initial report of this trial [2].
Crofelemer is the only drug specifically licensed to treat diarrhea in people with HIV. The double-blind placebo-controlled ADVENT trial found a significantly greater response rate in the crofelemer group (17.6% versus 8.0%, P = 0.01). But ADVENT investigators believe the primary efficacy parameter in that trial was too stringent. Since participants began the trial with an average 20 watery stools weekly, meeting the responder definition required a 90% reduction in watery stools. The researchers think participants reap a "substantial clinical benefit" with a 50% or greater reduction in watery stools. Therefore they reanalyzed trial data with different outcomes.
Endpoints in the new analysis were (1) average decrease in number of watery stools per week across the study population and (2) proportion of participants who achieved "clinically relevant thresholds" of 50%, 75%, and 100% drops in number of watery stools.
Trial participants had noninfectious diarrhea for at least 1 month before enrolling while taking a stable antiretroviral regimen. Everyone entered the study with at least 100 CD4 cells. This analysis included participants who got 125 mg of crofelemer or placebo for 4 weeks, all of whom could then take crofelemer for the next 20 weeks. Thus participants took crofelemer for 24 or 20 weeks.
The analysis involved 136 people randomized to crofelemer and 138 randomized to placebo. Age averaged around 45 years and about 84% were men. Whites made up about 40% of the population, blacks 38%, and Hispanics 20%. These people had diarrhea for an average 6 years and reported an average 20 watery stools weekly. Most participants, 59%, had already used at least one antidiarrheal medication. About 80% of people completed the placebo-free extension phase.
Researchers attributed 75% of diarrhea cases to antiretroviral therapy and 25% to HIV infection of the intestine or other causes. After 1 week or crofelemer, participants experienced an average 29% decrease in watery stools. That proportion rose to 63% after 8 weeks and to 66% after 20 weeks. After 4, 12, and 20 weeks, proportions reporting a 100% reduction in watery stools were 15%, 41%, and 50%. Respective proportions reporting a 75% reduction were 35%, 60%, and 63%. And respective proportions reporting a 50% reduction were 48%, 72%, and 73%.
Response rates did not differ by whether participants were taking a protease inhibitor or whether their diarrhea resulted from antiretroviral therapy or from HIV and other causes.
ADVENT investigators attributed no serious adverse events to crofelemer. The most frequent adverse events were upper respiratory tract infection (5.7%), bronchitis (3.9%), cough (3.5%), flatulence (3.1%), and increased bilirubin (3.1%).
Because diarrhea affects about 20% of the 36 million people with HIV worldwide, the researchers estimate that more than 7 million people may benefit from crofelemer therapy.
References
1. MacArthur RD, Clay P, Blick G, et al. Long-term crofelemer provides clinically relevant reductions in HIV-related diarrhea. 9th IAS Conference on HIV Science (IAS 2017), July 23-26, 2017, Paris. Abstract WEPEB0537.
2. MacArthur RD, Hawkins TN, Brown SJ, et al. Efficacy and safety of crofelemer for noninfectious diarrhea in HIV-seropositive individuals (ADVENT trial): a randomized, double-blind, placebo-controlled, two-stage study. HIV Clin Trials. 2013;14:261-273.
Long-Term Crofelemer Provides Clinically Relevant Reductions in HIV-Related Diarrhea
Rodger D. MacArthur, MD1; Patrick Clay, PharmD2; Gary Blick, MD3; Roger Waltzman, MD4; Margie Bell, MS5
1Medical College of Georgia, Augusta, GA; 2University of North Texas Health Science Center, Fort Worth, TX; 3Health Care Advocates International, LLC, Stratford, CT; 4Rgenix, New York, NY; 5ClinData Services, Inc., Fort Collins, CO
Long-Term Crofelemer Provides Clinically Relevant Reductions in HIV-Related Diarrhea
Rodger D. MacArthur, MD1; Patrick Clay, PharmD2; Gary Blick, MD3; Roger Waltzman, MD4; Margie Bell, MS5
1Medical College of Georgia, Augusta, GA; 2University of North Texas Health Science Center, Fort Worth, TX; 3Health Care Advocates International, LLC, Stratford, CT; 4Rgenix, New York, NY; 5ClinData Services, Inc., Fort Collins, CO
References
1. Crofelemer [package insert]. San Francisco, CA: Napo Pharmaceuticals, Inc.; 2016.
2. MacArthur RD, Hawkins TN, Brown SJ, et al. Efficacy and safety of crofelemer for noninfectious diarrhea in HIV-seropositive individuals (ADVENT trial): a randomized, double-blind, placebo-controlled, two-stage study. HIV Clin Trials. 2013;14(6):261-273.
3. Gehrig M, Clay P, Perry R, et al. Actual versus perceived use of pharmacokinetic (primarily absorption) influential OTC agents and ART tolerability in a nationwide matched cohort of HIV patients and their healthcare providers. Poster abstract presented at: ID Week 2016; October 26-30, 2016; New Orleans, LA. Abstract 1514.
4. World Health Organization. Global Health Observatory data: HIV/AIDS. Available at http://www.who.int/gho/hiv/en/. Accessed May 25, 2017.
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