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Supplements Addressing Adherence Challenges Associated With Antiretroviral Therapy: Focus on Noninfectious Diarr
Participating Faculty: Addressing Adherence Challenges Associated With Antiretroviral Therapy: Focus on Noninfectious Diarrhea
The Importance of Treatment Adherence in HIV
Kenneth L. Schaecher, MD, FACP, CPC
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Management of Noninfectious Diarrhea Associated With HIV and Highly Active Antiretroviral Therapy
Rodger D. MacArthur, MD

Management of Noninfectious Diarrhea Associated With HIV and Highly Active Antiretroviral Therapy

Rodger D. MacArthur, MD
The safety data, which included study subjects from both the first and second phases of the study (crofelemer n = 130, placebo n = 137), showed that the percentages of patients who experienced any adverse event (AE) were similar in the crofelemer and placebo groups (34.6% crofelemer vs 32.8% placebo), and the rate of serious AEs was very low and similar for both groups (1.5% crofelemer vs 2.9% placebo). There were 4 serious AEs (any cause) in the placebo group and 2 in the crofelemer group, and 4 AE-related discontinuations in the placebo group compared with none in the crofelemer group. GI effects and infections were the most common AEs in both groups, and 2 cases each of the following AEs were observed in the crofelemer group: dyspepsia, flatulence, abdominal pain, hemorrhoids, and constipation. Upper respiratory tract infections were seen in 5 crofelemer and 4 placebo patients, while urinary tract infections were seen in 3 crofelemer patients and 1 placebo patient.31

Other Non-Approved and Non-Pharmacologic Treatments

Octreotide—The somatostatin analogue octreotide has demonstrated efficacy in patients with HIV and AIDS experiencing diarrhea. However, studies of octreotide have largely been conducted in the pre-HAART era, and do not reflect treatment of HAART-induced diarrhea.33-35

Racecadotril—The enkephalinase inhibitor racecadotril (also known as acetorphan) has demonstrated efficacy in small studies of patients with HIV experiencing diarrhea, but the data are limited and do not reveal the efficacy of racecadotril in HAART-related diarrhea.34,36

Bovine colostrum—Bovine colostrum has been shown to alleviate diarrhea in HIV-positive patients in several studies. However, these studies were conducted in patients who were, for the most part, not receiving HAART, or whose diarrhea predated initiation of HAART, and its efficacy in HAART-treated patients is therefore unclear.37-39

Curcumin—Curcumin (extracted from turmeric) as a treatment for HIV-related diarrhea was evaluated in a nonblinded, non-controlled study by the Southern California Kaiser Permanente Medical Group in 8 patients in whom no pathogen or parasite was detected by stool culture or observation or by endoscopy or colonoscopy. Seven of the 8 subjects were receiving HAART. The mean number of bowel movements before therapy was 6.75, which was reduced to 1.69 by the end of therapy (P = .006). Time to resolution varied from 3 to 28 days; side effects were minimal and not serious.40

Lactobacillus rhamnosus GG—The effects of the probiotic Lactobacillus rhamnosus GG (LGG) were evaluated in 17 patients with HIV-related diarrhea in a randomized, placebo-controlled study with crossover design (2 weeks on LGG and 2 weeks on placebo) conducted in Finland. Neither daily stool frequency nor bowel movements were statistically different between LGG and placebo, nor did LGG improve stool consistency.41


The success of HAART in reducing HIV/AIDS morbidity and mortality also conferred a substantial reduction in the risk of the kind of opportunistic infection that can ravage patients and considerably speed their deterioration. The success of these treatments should not, however, overshadow the fact that diarrhea remains a serious problem in the HAART era, particularly with regard to certain drugs and drug classes. Diarrhea can adversely impact QoL. Knowledge of the serious impact of diarrhea in patients with HIV should prompt the selection of therapies to minimize diarrhea risk. In cases when diarrhea is unavoidable, the recent approval of crofelemer provides a therapeutic option for a substantial proportion of the affected patient population.

Author affiliations: Department of Internal Medicine, Division of Infectious Diseases, Wayne State University and Wayne State University HIV/AIDS Clinical Research Unit, Detroit, MI.
Funding source: This supplement was supported by Salix Pharmaceuticals, Inc.
Author disclosure: Dr MacArthur reports providing expert testimony on behalf of Salix Pharmaceuticals, Inc. He also reports meeting/conference attendance with Salix Pharmaceuticals, Inc.
Authorship information: Concept and design; acquisition of data; analysis and interpretation of data; critical revision of the manuscript for important intellectual content; and supervision.
Address correspondence to: Rodger D. MacArthur, MD, WSU Tolan Park Medical Building, 3901 Chrysler Service Drive, Suite 4B, Detroit, MI. E-mail:
  1. Sharpstone D, Gazzard B. Gastrointestinal manifestations of HIV infection. Lancet. 1996;348(9024):379-383.
  2. Wilcox CM, Saag MS. Gastrointestinal complications of HIV infection: changing priorities in the HAART era. Gut. 2008;57(6):861-870.
  3. MacArthur RD, DuPont HL. Etiology and pharmacologic management of noninfectious diarrhea in HIV-infected individuals in the highly active antiretroviral therapy era. Clin Infect Dis. 2012;55(6):860-867.
  4. Feasey NA, Healey P, Gordon MA. Review article: the aetiology, investigation and management of diarrhoea in the HIVpositive patient. Aliment Pharmacol Ther. 2011;34(6):587-603.
  5. Tinmouth J, Kandel G, Tomlinson G, et al. Systematic review of strategies to measure HIV-related diarrhea. HIV Clin Trials. 2007;8(3):155-163.
  6. National Institute of Allergy and Infectious Diseases. Division of AIDS table for grading the severity of adult and pediatric adverse events. Division of AIDS Regulatory Support Group website. Accessed July 20, 2013.
  7. 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(5):484-490.
  8. Zingmond DS, Kilbourne AM, Justice AC, et al. Differences in symptom expression in older HIV-positive patients: the Veterans Aging Cohort 3 Site Study and HIV Cost and Service Utilization Study experience. J Acquir Immune Defic Syndr. 2003;33(suppl 2):S84-S92.
  9. Harding R, Lampe FC, Norwood S, et al. Symptoms are highly prevalent among HIV outpatients and associated with poor adherence and unprotected sexual intercourse. Sex Transm Infect. 2010;86(7):520-524.
  10. Al-Dakkak I, Patel S, McCann E, et al. The impact of specific HIV treatment-related adverse events on adherence to antiretroviral therapy: a systematic review and meta-analysis. AIDS Care. 2013;25(4):400-414.
  11. Duran S, Spire B, Raffi F, et al. Self-reported symptoms after initiation of a protease inhibitor in HIV-infected patients and their impact on adherence to HAART. HIV Clin Trials. 2001;2(1):38-45.
  12. Prosperi MC, Fabbiani M, Fanti I, et al. Predictors of first-line antiretroviral therapy discontinuation due to drug-related adverse events in HIV-infected patients: a retrospective cohort study. BMC Infect Dis. 2012;12:296.
  13. Cadosch D, Bonhoeffer S, Kouyos R. Assessing the impact of adherence to anti-retroviral therapy on treatment failure and resistance evolution in HIV. J R Soc Interface. 2012;9(74):2309-2320.
  14. Gardner EM, Sharma S, Peng G, et al. Differential adherence to combination antiretroviral therapy is associated with virological failure with resistance. AIDS. 2008;22(1):75-82.
  15. Bacha T, Tilahun B, Worku A. Predictors of treatment failure and time to detection and switching in HIV-infected Ethiopian children receiving first line anti-retroviral therapy. BMC Infect Dis. 2012;12:197.
  16. Hill A, Balkin A. Risk factors for gastrointestinal adverse events in HIV treated and untreated patients. AIDS Rev. 2009;11(1):30-38.
  17. Tramarin A, Parise N, Campostrini S, et al. Association between diarrhea and quality of life in HIV-infected patients receiving highly active antiretroviral therapy. Qual Life Res. 2004;13(1):243-250.
  18. Rufo PA, Lin PW, Andrade A, et al. Diarrhea-associated HIV-1 APIs potentiate muscarinic activation of Cl- secretion by T84 cells via prolongation of cytosolic Ca2+ signaling. Am J Physiol Cell Physiol. 2004;286(5):C998-C1008.
  19. Braga Neto MB, Aguiar CV, Maciel JG, et al. Evaluation of HIV protease and nucleoside reverse transcriptase inhibitors on proliferation, necrosis, apoptosis in intestinal epithelial cells and electrolyte and water transport and epithelial barrier function in mice. BMC Gastroenterol. 2010;10:90.
  20. HIV and AIDS--medicines to help you. US Food and Drug Administration website. Accessed July 21, 2013.
  21. Raffi F, Rachlis A, Stellbrink HJ, et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, noninferiority SPRING-2 study. Lancet. 2013;381(9868):735-743.
  22. Beatty GW. Diarrhea in patients infected with HIV presenting to the emergency department. Emerg Med Clin North Am. 2010; 28(2):299-310.
  23. Sherman DS, Fish DN. Management of protease inhibitor-associated diarrhea. Clin Infect Dis. 2000;30(6):908-914.
  24. Fulyzaq [prescribing information]. Raleigh, NC: Salix Pharmaceuticals; February 2013.
  25. Cottreau J, Tucker A, Crutchley R, Garey KW. Crofelemer for the treatment of secretory diarrhea. Expert Rev Gastroenterol Hepatol. 2012;6(1):17-23.
  26. 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(10):1121-1129.
  27. MacArthur RD, Hawkins T, Brown SJ, et al. ADVENT trial: crofelemer for the treatment of secretory diarrhea in HIV+ individuals [poster 889]. Conference on Retroviruses and Opportunistic Infections; March 5-8, 2012; Seattle, WA.
  28. Gao W-Y. Application number: 202292Orig1s000. Medical review(s). Published 2012. Accessed July 22, 2013.
  29. Crutchley RD, Miller J, Garey KW. Crofelemer, a novel agent for treatment of secretory diarrhea. Ann Pharmacother. 2010; 44(5):878-84.
  30. Holodniy M, Koch J, Mistal M, et al. A double blind, randomized, placebo-controlled phase II study to assess the safety and efficacy of orally administered SP-303 for the symptomatic treatment of diarrhea in patients with AIDS. Am J Gastroenterol. 1999;94(11):3267-3273.
  31. MacArthur RD, Hawkins T, Brown SJ, et al. Safety and tolerability of crofelemer 125 mg for treating non-infectious diarrhea in HIV+ individuals: results from double-blind and open-label studies [poster 787]. Conference on Retroviruses and Opportunistic Infections; March 3-6, 2013; Atlanta, GA.
  32. MacArthur RD, Clay PG, Barrett AC, et al. Identifying high responder populations to crofelemer for treatment of noninfectious diarrhea in HIV+ individuals [poster H-1264]. Interscience Conference on Antimicrobial Agents and Chemotherapy; September 10-13, 2013; Denver, CO.
  33. Neild PJ, Evans DF, Castillo FD, et al. Effect of octreotide on small intestinal motility in HIV-infected patients with chronic refractory diarrhea. Dig Dis Sci. 2001;46(12):2636-2642.
  34. Beaugerie L, Baumer P, Chaussade S, et al. Treatment of refractory diarrhoea in AIDS with acetorphan and octreotide: a randomized crossover study. Eur J Gastroenterol Hepatol. 1996;8(5):485-489.
  35. Romeu J, Miró JM, Sirera G, et al. Efficacy of octreotide in the management of chronic diarrhoea in AIDS. AIDS. 1991;5(12):1495-1499.
  36. Baumer P, Duvivier C, Bérard H, et al. HIV-related diarrhea: efficacy of acetorphan in a randomized controlled trial [abstract]. Gastroenterology. 1995;108(4):A778.
  37. Kaducu FO, Okia SA, Upenytho G, Elfstrand L, Florén CH. Effect of bovine colostrum-based food supplement in the treatment of HIV-associated diarrhea in Northern Uganda: a randomized controlled trial. Indian J Gastroenterol. 2011;30(6):270-276.
  38. Florén CH, Chinenye S, Elfstrand L, Hagman C, Ihse I. ColoPlus, a new product based on bovine colostrum, alleviates HIV-associated diarrhoea. Scand J Gastroenterol. 2006;41(6):682-686.
  39. Rump JA, Arndt R, Arnold A, et al. Treatment of diarrhoea in human immunodeficiency virus-infected patients with immunoglobulins from bovine colostrum. Clin Investig. 1992;70(7): 588-594.
  40. Conteas CN, Panossian AM, Tran TT, Singh HM. Treatment of HIV-associated diarrhea with curcumin. Dig Dis Sci. 2009;54(10):2188-2191.
  41. Salminen MK, Tynkkynen S, Rautelin H, et al. The efficacy and safety of probiotic Lactobacillus rhamnosus GG on prolonged, noninfectious diarrhea in HIV patients on antiretroviral therapy: a randomized, placebo-controlled, crossover study. HIV Clin Trials. 2004;5(4):183-191.
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