1. Rodger D. MacArthur, MD Professor of Medicine Division of Infectious Diseases Wayne State University Director and Site Principal Investigator Wayne State University HIV/AIDS Clinical Research Unit Detroit, Michigan Clinical Focus: Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients This program is supported by an educational grant from Image: 3D4Medical/Copyright©2013 Science Source. All Rights Reserved Jointly sponsored by the Annenberg Center for Health Sciences at Eisenhower and Clinical Care Options, LLC

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3. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients Faculty Disclosures Rodger D. MacArthur, MD, has disclosed that he has received consulting fees and fees for non-CME/CE services from Salix.

4. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients Prevalence of HIV-Associated Diarrhea  Changes in etiology since introduction of HAART (mid-1990s) –Infectious diarrhea –Noninfectious diarrhea  50% to 60% reported in earlier studies [1-3]  Prevalence in HAART era less clear –Acute diarrhea: 28% vs 7% of controls [4] –30% of pts on HAART; 70% of those noninfectious in HRQoL analysis [4] –Chronic diarrhea: 28% of 671 patients in a noncomparative trial [5] 1. Mathews WC, et al. Med Care. 2000;38:750-762. 2. Zingmond DS, et al. J Acquir Immune Defic Syndr. 2003;33(suppl 2):S84-S92. 3. Eisenberg JN, et al. Epidemiol Infect. 2002;128:73-81.4. Siddiqui U, et al. J Clin Gastroenterol. 2007;41:484-490. 5. Knox TA, et al. Am J Gastroenterol. 2000;95:3482-3489.

5. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients Defining Diarrhea  ≥ 3 unformed stools/day or liquid stool volume > 200 g/day [6]  Chronic diarrhea ≥ 4 wks  Grading diarrhea (CTCAE criteria) [7] –1: increase of < 4 stools/day over baseline –2: increase of 4-6 stools/day over baseline –3: increase of ≥ 7 stools/day over baseline; incontinence; hospitalization indicated –4: life-threatening consequences requiring urgent intervention –5: death 6. MacArthur RD, et al. Clin Infect Dis. 2012;55:860-867. 7. DHHS. CTCAE 2010.

6. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients Defining Noninfectious Diarrhea  Not related to an infectious agent  Noninfectious disease causes –Antiretroviral related –HIV enteropathy 8. MacArthur RD, et al. Clin Infect Dis. 2012;55:860-867.

7. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients Diarrhea-Related QoL Effects  Medical Outcomes Study findings [11,12] –Diarrhea significantly more common by various criteria vs HIV-negative controls –Lower MOS SF-36 scores in all domains vs controls –Lower MOS-HIV scores in all domains in patients with diarrhea vs those without  Psychosocial effects [13,14] –Perceived QoL –Life controlled by diarrhea –Feelings of shame –Fear what diarrhea is doing to me 11. Tramarin A, et al. Qual Life Res. 2004;13:243-250. 12. Siddiqui U, et al. J Clin Gastroenterol. 2007;41:484-490. 13. Lorenz KA, et al. Ann Intern Med. 2001;134:854-860. 14. Siegel K, et al. J Pain Symptom Manage. 2010;40:353-369.

8. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients Diagnosing Noninfectious Diarrhea  Seroconversion-related diarrhea –High HIV-1 RNA, declining CD4+ cell count  More likely with CD4+ cell count > 200 cells/mm 3  Exclude infectious etiologies  GI malignancies  With successful antiretroviral therapy –Less infectious diarrhea –More treatment-related diarrhea

9. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients Diagnostic and Management Algorithm 15. MacArthur RD, et al. Clin Infect Dis. 2012;55:860-867. Patient with HIV and diarrhea History and physical exam Duration of diarrhea Stool examination  3 samples over 10 days CD4+ cell count HIV-1 RNA Treat accordingly HIV enteropathy Supportive treatment Flexible sigmoidoscopy Colonoscopy with terminal ileostomy Upper endoscopy Review ART Radiologic evaluation of neoplastic lesions Pathogen identified No pathogen identified Condition diagnosed No diagnosis

10. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients HIV Enteropathy  Idiopathic diarrhea, occurring at any time from acute to advanced HIV infection  Pathogenic mechanisms –Direct HIV effects on GI cells –HIV-related activation of GI immune system and GALT 16. MacArthur RD, et al. Clin Infect Dis. 2012;55:860-867.

11. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients Reprinted by permission from Macmillan Publishers Ltd: Mucosal Immunol. Brenchley JM, Douek DC. HIV infection and the gastrointestinal immune system. Mucosal Immunol. 2008;1:23-30. HIV-Associated Damage to the GI Tract a) A healthy GI tract with villi, crypts, macrophages, dendritic cells, maintenance of the epithelial barrier, T cells, B cells, and luminal defensin peptides. b) A chronically HIV-infected GI tract with 1) blunted villi, 2) crypt hyperplasia, 3) damage to the epithelial barrier with enterocyte apoptosis, 4) decreased luminal defensin, 5) massive CD4 T-cell depletion, 6) high frequencies of infected CD4 T cells with release of virions, 7) microbial translocation, and 8) increased permeability.

12. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients Etiology of ARV-Associated Diarrhea  Opportunistic infections less common with CD4+ cell count > 200 cells/mm 3  ARVs associated with noninfectious diarrhea –PIs –EFV –TDF –EVG/COBI/FTC/TDF  Possible mechanisms of ARV-associated diarrhea [18] –Calcium-dependent chloride conductance –Cellular apoptosis –Necrosis –Proliferation of intestinal epithelial cells 18. Bode H, et al. Antivir Ther. 2005;10:645-655.

13. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients Incidence of ARV-Associated Diarrhea ARV ClassReported Incidence of Diarrhea, % PIs  LPV/RTV BID  ATV/RTV  DRV/RTV 7-28 2-3 9-14 NNRTIs  EFV  NVP  RPV 3-14 < 1-2 < 2 NRTIs  TDF  ABC 9-16 7 INSTIs  RAL  DTG  EVG* < 1 ~ 1 12 *Coformulated elvitegravir/cobicistat/emtricitabine/tenofovir.

14. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients Other Etiologies  Autonomic neuropathy [19]  Pancreatitis [19]  Irritable bowel syndrome  HIV-related malignancies [19] –Kaposi’s sarcoma –Non-Hodgkin’s lymphoma 19. Feasey NA, et al. Aliment Pharmacol Ther. 2011;34:587-603.

15. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients ARV Regimen Switch as Treatment  Key considerations in deciding to switch ART regimen –Tolerability of new regimen –Probable efficacy of new vs current regimen –Switch from one ARV class to another  Example: –Significant reduction in treatment-related diarrhea reported in patients switching from PI-based to EFV-based therapy [20] –From 52% at baseline to 32% of patients at Wk 48 20. DeJesus E, et al. J Acquir Immune Defic Syndr. 2009;51:163-174.

16. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients Pharmacologic Treatments  Adsorbents –Evidence for utility largely anecdotal –Attapulgite –Clay mineral containing aluminum and magnesium silicates –Bismuth subsalicylate –Rare risk of bismuth encephalopathy in persons with advanced HIV disease –Kaolin* –Fine white clay of hydrated aluminum silicate –Pectin* 22. Nwachukwu CE, et al. Cochrane Database Syst Rev. 2008;4:CD005644. *Removed from market following 2003 FDA review panel determination of insufficient efficacy data.

17. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients Pharmacologic Treatments  Antimotility agents [24] –Diphenoxylate-atropine [25] –5 mg QID –Loperamide [25] –4 mg, then 2 mg; max 16 mg/day 24. Nwachukwu CE, et al. Cochrane Database Syst Rev. 2008;4: CD005644. 25. Sherman DS, et al. Clin Infect Dis. 2000;30:908-914.

18. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients Pharmacologic Treatments  Antisecretory agents –Octreotide [26,27] –Somatostatin analogue, inhibits GI hormone production –Subcutaneous injection –Crofelemer –Derived from tropical tree –Licensed in December 2012 for symptomatic relief of diarrhea in adults receiving ART 26. Beaugerie L, et al. Eur J Gastroenterol Hepatol. 1996;8:485-489. 27. Montaner JS, et al. AIDS. 1995;9:209-210.

19. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients Crofelemer: Phase III ADVENT Study 30. MacArthur, et al. CROI 2012. Abstract 889. Endpoints Weekly response: proportion with ≤ 2 watery stools/wk Monthly response: proportion with ≤ 2 watery stools/wk for ≥ 2 of 4 wks in 1 mo HIV-infected patients receiving ART, CD4+ cell count > 100 cells/mm 3, no intestinal pathogens, watery bowel movement ≥ 5 of 7 days before enrollment (N = 376) Crofelemer 125 mg BID (n = 136) Crofelemer 250 mg BID (n = 54) Crofelemer 500 mg BID (n = 46) Placebo BID (n = 138) Crofelemer 125 mg BID (n = 92) Placebo BID (n = 136) Stage 1: 4 WksStage 2: 5 Mos

20. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients ADVENT: Response to Crofelemer vs Placebo  Response rate in placebo recipients who crossed over to crofelemer during 5-mo extension: 36% vs 9% after 1 mo (P <.0001)  Adverse events, crofelemer vs placebo: –Any AE: 27% vs 33% –Serious AE: 2% vs 3% –Discontinuation due to AE: 0% vs 3% 31. MacArthur, et al. CROI 2012. Abstract 889. 25 20 15 10 5 0 Patients With ≤ 2 Watery Stools/wk for ≥ 2 of 4 Wks in Mo (%) Stage 1Stage 2Combined Response Crofelemer 125 mg Crofelemer 250 mg Crofelemer 500 mg Placebo P =.0096 9/44 5/54 9/46 1/50 15/92 10/88 24/136 11/138

21. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients ADVENT: Response in Subpopulations Monthly Response Rates in Specific Populations 32. MacArthur, et al. ICAAC 2013. Abstract H-1264. 20 18 16 14 12 0 10 8 6 4 2 Crofelemer Placebo Diarrhea > 2 yrs > 2 Watery Stools/D Stool Consistency Score > 4 Other Antidiarrheal Used, Last 4 Wks Use Of PI-Based Therapy Patients (%) 17/91 7/92 9/75 2/83 19/111 10/119 15/87 6/97 7/47 0/53

22. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients Experimental Therapies  Serum bovine immunoglobulin supplement [33] –Protein isolate of bovine plasma  Mesalamine [34] –Salicylate antiinflammatory agent for treatment of ulcerative colitis, proctitis  Cholestyramine [35] –Synthetic resin 33. Asmuth DM, et al. AIDS. 2013;[Epub ahead of print]. 34. Rodriguez-Torres M, et al. Dig Dis Sci 2006;51:161-167. 35. Steuerwald M, et al. Am J Gastroenterol. 1995;90:2051-2053.

23. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients Dietary Modification  Fiber supplementation [37] –Oat bran –Psyllium  Medium-chain triglyceride diet [38] –Do not require bile salts for digestion –High in calories, easily digested –Found in palm kernel oil, coconut oil 36. Anastasi JK, et al. J Assoc Nurses AIDS Care. 2006;17:47-57. 37. Sherman DS, et al. Clin Infect Dis. 2000;30:908-914. 38. Wanke CA, et al. Nutrition. 1996;12:766-771.  General principles [36] –Avoid: spicy, highly seasoned foods; caffeine; carbonated drinks; fried foods –BRAT diet –Maintain hydration

24. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients Micronutrient Supplementation  Curcumin [39] –Decrease in mean number of bowel movements/day from 7.0 to 1.7  Zinc [40] –No significant difference in discontinuation of diarrhea 39. Conteas CN, et al. Dig Dis Sci. 2009;54:2188-2191. 40. Carcamo C, et al. J Acquir Immune Defic Syndr 2006; 43:197-201.

25. clinicaloptions.com/hiv Evolving Options for Managing Noninfectious Diarrhea in HIV-Infected Patients Summary  HIV-related diarrhea in the HAART era –Decreased incidence of infectious causes –Increased incidence of noninfectious diarrhea  Causes –Antiretroviral [ARV]-related, especially PIs –HIV enteropathy –Noninfectious diseases (pancreatitis, malignancies, IBD)  QoL effects –Sense of shame –Greater disability  Management –ARV switch, eg, PI to NNRTI –Pharmacologic therapy, eg, antimotility agents (loperamide), antisecretory agents (crofelemer, octreotide) –Diet, eg, BRAT diet, fiber supplements, caffeine avoidance

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