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Supplements Addressing Adherence Challenges Associated With Antiretroviral Therapy: Focus on Noninfectious Diarr
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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
If no pathogen has been identified, and the diarrhea has persisted, and is severe (ie, at least 10 abnormal stools in 24 hours), endoscopic examination of the GI tract may be appropriate to rule out observable causes such as cytomegalovirus (CMV) colitis, microsporidial infection, or giardia. The greater the diarrhea severity and the lower the CD4+ count, the stronger the rationale for endoscopic examination.3,4
  1. Upper endoscopy and flexible sigmoidoscopy or colonoscopy are viable endoscopic modalities to procure samples for biopsy; full colonoscopy, ideally with terminal ileoscopy, is recommended, particularly in cases of severe symptoms, and strongly recommended in cases of CD4+ cell count less than 100 cells per μL.3
  2. For patients with Kaposi’s sarcoma or non-Hodgkin lymphoma, radiologic imaging of the GI tract may be necessary to evaluate lesions. Radiologic imaging may also help identify edematous or ulcerated mucosa that could narrow a search for a pathogen, particularly in correlation with CD4+ count, but samples for biopsy must be obtained to confirm diagnosis.3,4


Stage 3: Evaluation of HAART Regimen

Clinical trials in ART have exhibited rates of grade 2 to 4 diarrhea ranging from 2% to 19%, with most trials being nearer the higher end of the range.16 Evidence exists for mechanisms by which ART may produce diarrhea in patients with HIV. For example, some ART agents are thought to potentiate stimulation of calcium-dependent chloride ion channels resulting in excess secretion in the human intestine.18 Certain drugs have also been shown to cause damage to the intestinal epithelial barrier—including reduction in villi length and crypt depth (components of the epithelial lining), and induction of apoptosis—causing intestinal permeability and leakage of water and electrolytes from the intestines.19

Because diarrhea as a side effect of HAART is a major contributor to the prevalence of noninfectious HIV-related diarrhea, an evaluation of the treatment regimen in patients with diarrhea should be undertaken. If HAART-related diarrhea is suspected at initial presentation, this diagnostic stage can precede stage 2.

Diarrhea has been shown to be a potential side effect of PIs, nucleoside reverse-transcriptase inhibitors, nonnucleoside reverse-transcriptase inhibitors, and integrase inhibitors.20-22 The PI ritonavir is particularly associated with diarrhea as a side effect, and while it is now used as a pharmacokinetic enhancer (“booster drug”) for other PIs, it remains a high-risk agent for diarrhea. Among ritonavir-inclusive HAART combinations, those most strongly associated with moderate (grade 2), severe (grade 3), and life-threatening (grade 4) diarrhea are lopinavir-ritonavir and fosamprenavir-ritonavir, while lower risks are associated with atazanavir-ritonavir, darunavir-ritonavir, and saquinavir-ritonavir. Several of these combinations are currently used as first-line treatment.3

If none of the above diagnostic stages reveal the cause of diarrhea, and if the diarrhea has remained persistent, consideration of HIV enteropathy as a diagnosis is appropriate. HIV enteropathy, it may be noted, describes idiopathic diarrhea, where no pathogen is identified and which may occur at any stage of HIV infection and AIDS. The histological evidence for HIV enteropathy includes blunting and atrophy of villi, hyperplasia of epithelial crypts, and inflammatory lymphocytic infiltration of the lamina propria, a layer of tissue lying below the epithelium. HIV enteropathy may or may not be ameliorated with HAART treatment.3

Therapeutic Options

General supportive care should be implemented in patients experiencing diarrhea, and over-the-counter medications may be employed. Over-the counter fiber additives, such as psyllium, commonly found at drugstores and health food stores, are recommended to ameliorate diarrhea.3 Incorporating fiber-rich foods into the diet is also advisable. These include leafy green vegetables, broccoli and cauliflower, oat bran, cabbage, celery, raspberries, and squash, as well as beans and legumes such as split peas, lentils, and black or lima beans.

A number of supportive agents, including adsorbent, antimotility, and antisecretory agents, have been used to help manage diarrhea. Bismusth subsalicylate, a commonly used adsorbent agent for diarrhea, may be risky for HIV-positive patients, particularly patients with more advanced disease, due to the (remote) risk of bismuth encephalopathy. Other adsorbent agents that improve stool consistency include attapulgite, kaolin, and pectin.3 Loperamide, an opioid derivative, possesses both antimotility and antisecretory properties, and has shown limited efficacy in a chart review that included 47 patients who were receiving treatment with nelfinavir. Diphenoxylate/atropine is another antimotility agent possessing opioid characteristics; there are limited clinical study data to support its use in patients experiencing diarrhea associated with PI therapy. Diphenoxylate/atropine, like other opioid-related drugs that are sometimes used for antimotility qualities, can be habit forming and, at higher doses, exhibit opioid analgesic activity.3,23

It should be noted that antimotility agents have not been studied for their safety in patients with HIV-related diarrhea, and do not treat the causes of diarrhea in patients with HIV; also, antimotility agents are associated with constipation. In addition, in an era of increasing prevalence of C difficile, extreme caution should be exercised prior to prescribing antimotility agents.

At present, only 1 agent, crofelemer, has been approved by the US Food and Drug Administration (FDA) (on December 31, 2012) for the treatment of noninfectious diarrhea in patients with HIV/AIDS receiving antiretroviral therapy.24 Crofelemer is a botanical compound derived from the stem bark latex of an Amazonian tree called the Croton lechleri, the red-colored latex being known as Sangre de Drago or Dragon’s Blood.25 The mechanism of action of crofelemer involves the inhibition of prosecretory intestinal chloride ion channels, which are a necessary part of intestinal fluid secretion (Figure 1).26,27 Interestingly, absorption of crofelemer is minimal in human subjects (with or without HIV infection), and more than 95% of subjects in pharmacokinetic studies had crofelemer levels below that quantifiable by standard assays.26 Crofelemer does not appear to confer risk of GI-absorption– based interactions, and is not associated with significant pharmacokinetic interaction with antiretroviral therapies.24,28

Prior to the pivotal phase 3 trial, ADVENT, upon which crofelemer’s FDA approval was based, crofelemer had been studied in other conditions, including traveler’s diarrhea and diarrhea-predominant irritable bowel syndrome (IBS). Crofelemer showed efficacy in conditions in which the diarrhea was secretory in nature (eg, traveler’s diarrhea) but did not demonstrate efficacy in IBS; the lack of efficacy in IBS may be due to the multifactorial nature of diarrhea in IBS.29 Crofelemer was also studied in a phase 2 trial for the treatment of diarrhea in patients with AIDS; the results were published in 1999. The phase 2 study population (N = 51), 77% of whom were receiving treatment with a PI, were randomized to crofelemer or placebo, and the investigators observed a significant reduction in both stool weight (P = .008) and stool frequency (P = .04) with crofelemer treatment.26,30

The recent ADVENT trial included HIV-positive subjects who were experiencing diarrhea for at least 4 weeks, were receiving ART, had a CD4+ cell count greater than 100 cells per μL, and showed no evidence of intraluminal pathogen-related diarrhea. The mean number of daily watery bowel movements in the study population was slightly less than 3, with a marginally higher rate (3.04) in the placebo-treated patients versus patients receiving crofelemer. Patients had received their HIV diagnosis an average of approximately 12.5 years prior to the study, and had been experiencing diarrhea for between 5.5 and 6.9 years. The mean age of the study subjects was 44 to 46 years, and the patient population was ethnically diverse.27

The trial was divided into 2 separate stages. The first stage was a dose evaluation study that established an optimal dose of 125 mg twice daily. The second stage, comprised of an entirely new set of subjects meeting the same entry criteria (crofelemer n = 92, placebo n = 88), was a double-blind, randomized, controlled trial with a 4-week blinded phase and a 20-week open-label extension in which all subjects were treated with crofelemer 125 mg twice daily. The primary end point for the 4-week blinded phase was response rate, where response was defined as no more than 2 watery bowel movements per week for 2 or more of the 4 weeks.26,27,31

At the end of the 4-week blinded phase, response rates for patients in the crofelemer groups were numerically superior compared with response rates for patients in the placebo group (16.3% vs 11.4%), and by week 4, the rate of response in crofelemer-treated patients was nearly double that of the placebo group (approximately 19% vs approximately 10%).27 The crofelemer response rate during the placebo-controlled period increased continuously throughout the 4 weeks, and continued to improve almost continuously throughout the 20-week open-label extension (n = 136), reaching a plateau of an approximately 50% response rate (Figure 2).31 Exploratory analyses of the outcomes data from the ADVENT trial revealed numerically higher response rates (reported as percentage differences comparing crofelemer-treated versus placebo-treated) in several subgroups of patients, including patients who had used antidiarrheal medications in the past 4 weeks versus those who had not used antidiarrheal medications (14.9% vs 6.2%), patients with CD4+ cell counts less than 404 cells/mm3 compared with those with higher CD4+ cell counts (15.6% vs 7.2%), patients diagnosed more than 12 years ago compared with those with a more recent diagnosis (14.1% vs 5.5%), and patients who used PIs compared with those who used other classes of antiretrovirals (11.0% vs 6.2%).32

 
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