Introduction

Advances in the treatment of human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) have transformed this disease into a chronic illness [1]. As a result, individuals with HIV have a longer life expectancy [2]. When HIV is treated early and aggressively, life expectancy approaches that of uninfected individuals [3, 4]. According to the Centers for Disease Control and Prevention (CDC), the annual incidence of HIV has remained stable during the past 10 years [2]. In 2010, the prevalence of HIV in individuals aged over 13 years was estimated to be about 1,148,200 [5]. Although this number illustrates a dramatic increase in the prevalence of HIV since 1996, it is largely due to the decreased mortality rate associated with the advent of antiretroviral therapy (ART) [2].

Because most cases of diarrhea in the pre-ART era were due to infectious pathogens, it was widely believed that successful treatment would reduce, or even solve, this problem [6, 7]. Although ART has improved the survival and quality of life of patients with HIV, and even decreased the incidence of diarrhea in this population, diarrhea remains a common complaint among these patients and continues to negatively impact the quality of life [6–9]. Furthermore, while the burden of diarrhea in the HIV-infected population remains high, the causes of diarrhea have shifted toward noninfectious etiologies [6, 7]. In one survey, ~60 % of patients receiving ART reported having the symptom of diarrhea in the previous month [10]; clinical trial data would suggest that up to 19 % of these events may have been due to the effects of ART itself [11]. In support of this assertion, US historical data of HIV-infected patients with CD4+ T cell counts <200 cells/mm3 were investigated and demonstrated a decline in infectious diarrhea from 53 to 13 % over 3 years (1995–1997); this correlated with the introduction of ART around 1995 [6]. During that same period, the percentage of patients with noninfectious diarrhea increased from 32 to 71 % [6]. A similar trend in etiologic differences has been observed in other countries for patients taking ART versus those not taking ART [12]. This review explores some explanations for the continued burden of diarrhea among patients with HIV, discusses the diagnostic workup, and provides guidance on how HIV-associated noninfectious diarrhea should be treated.

Pathophysiology

HIV Infection of the Gastrointestinal Tract

Gut-associated lymphoid tissue (GALT) is the largest collection of lymphoid tissue in the human body [13]. The gastrointestinal (GI) tract is regularly exposed to a complex and diverse assortment of antigens from both microbial and dietary sources [14]. As a result, naïve B and T cells of the gut are constantly interacting with antigens that induce their maturation into plasma cells and memory T cells, respectively. This persistent stimulation of the immune system leads to a baseline inflammatory state that encourages the production of chemokines and adhesion molecules, which mediate the movement of lymphocytes into the mucosal tissues [13, 15]. The GI tract is targeted during all phases of HIV infection, but the effects of HIV on the mucosal immune system are most apparent in the acute infection period. Data from simian models with simian immunodeficiency virus [16] and from patients with HIV [13, 17, 18] show that within weeks of infection, the vast majority of mucosal lamina propria CD4+ lymphocytes are depleted. This depletion occurs well before any decrease in CD4+ T cells is seen in the periphery and likely reflects the greater expression of the CC chemokine receptor type 5 (CCR5), which functions as the primary coreceptor for the majority of infective HIV strains, on mucosal CD4+ T cells [19]. The expression of the chemokine receptor on these cells supports the entry of the virus, but their state of physiologic activation is responsible for enhanced HIV replication in the mucosal compartment and subsequent mucosal CD4+ T cell depletion. Further, despite the use of potent antiretroviral medications, HIV persists within GALT lymphocytes, even after repletion of CD4+ T cells in the periphery [20]. Thus, in patients with chronic HIV infection, the mucosal environment contains a paucity of CD4+ T cells but is overpopulated with CD8+ T cells and B cells, giving the wrong impression of a healthy mucosal environment at the microscopic level [21].

The etiology of diarrhea in HIV-infected patients can be divided into two major categories: noninfectious and infectious. As treatment of HIV has improved, the increase in peripheral CD4+ T cell counts has resulted in a decline in the risk of infection and associated diarrhea (Fig. 1) [22]. Indicative of this shift, noninfectious etiologies of diarrhea have now surpassed infectious causes [6]. Noninfectious diarrhea is defined as pathogen-negative diarrhea and includes ART-associated diarrhea, GI damage related to HIV infection (i.e., HIV enteropathy), and many causes mirroring those seen in gender- and age-matched patients without HIV infection.

Fig. 1
figure 1

Common causes of diarrhea at different stages of HIV infection and treatment. The shaded boxes indicate causes of diarrhea at different stages of HIV infection based on CD4+ T cell count. The impact of starting ART on CD4+ T cell counts is depicted by the gray dotted line. ART antiretroviral therapy, CMV cytomegalovirus, GI gastrointestinal, HIV human immunodeficiency virus, MAC Mycobacterium avium complex. Reprinted with permission from [22]

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Noninfectious Etiologies of Diarrhea

HIV Enteropathy

HIV enteropathy is an idiopathic form of diarrhea observed in patients with HIV in the absence of an infectious source with characteristic histologic features (Table 1) [8, 23–25]. While the exact mechanisms by which these changes occur in the GI tract are unclear, HIV has been postulated to alter signaling and cellular structure, which may lead to architectural distortion [23]. Several studies have demonstrated crypt epithelial proliferation in response to HIV infection, leading to increased crypt height, subsequent crypt cell encroachment onto villi, and relative decreased villous height resulting in diarrhea and malabsorption [26, 27]. A study by Keating and colleagues that investigated monosaccharide absorption in patients with HIV and AIDS demonstrated that patients with diarrhea had significant malabsorption of all monosaccharides tested [28]. Evidence of malabsorption was reported in patients with both pathogen-negative (n = 7) and pathogen-positive (n = 27) diarrhea, suggesting that malabsorption may be involved in HIV enteropathy, as well as in pathogen-induced diarrhea.

Table 1 Idiopathic diarrhea in patients with HIV
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Other hypotheses for the mechanism of HIV enteropathy include decreased transepithelial electrical resistance, decreased sodium-dependent glucose absorption, and increased intercellular permeability in HIV-infected cells [29]. In vitro studies have demonstrated that gp120, an envelope protein of HIV, induces microtubule disruption, decreases epithelial resistance, and promotes calcium signaling within the cell to affect these cytopathic changes [29, 30]. However, there was no effect of gp120 on chloride secretion.

HIV enteropathy may occur at all stages of HIV infection, from acute HIV to advanced AIDS [23]. Data suggest that HIV may be capable of infecting mucosal epithelial cells, resulting in direct effects on epithelial cell function [31]. Further, microscopic inflammation may be mechanistically involved in HIV enteropathy [23]. While HIV rapidly and severely depletes mucosal T cells, the total mucosal T cell population remains largely unchanged [21]. This reflects greater mucosal infiltration by activated CD8+ T cells. These cells are primed to produce proinflammatory cytokines and chemokines, which may directly damage the mucosal barrier, resulting in decreased transepithelial resistance and diarrhea [21, 23]. This has been shown to lead to malabsorption of vitamin B12, bile acid, and monosaccharides; thus, HIV enteropathy can also be more specifically defined by its physiologic effect on small bowel function [23, 28].

ART-Associated Diarrhea

While diarrhea is an adverse effect of ART, protease inhibitors seem to be most strongly associated with diarrhea (Table 2) [32]. In mouse models, protease inhibitors and reverse transcriptase inhibitors were found to significantly increase water and electrolyte secretion into the intestinal lumen in vivo [33]. Rufo and colleagues demonstrated that protease inhibitors in general and nelfinavir in particular potentiate signaling through muscarinic- and calcium-dependent receptors of intestinal cells, resulting in increased chloride secretion into the lumen [34]. This study also showed that sodium and chloride concentrations in stool samples from patients with HIV taking nelfinavir were elevated, consistent with secretory diarrhea. In an in vitro study, Bode and colleagues found that protease inhibitors induced apoptosis of human intestinal epithelium, compromising barrier function in the cells and thereby increasing water secretion in the gut lumen [35]. Wu and colleagues also investigated the mechanism by which protease inhibitors cause diarrhea and found that lopinavir and ritonavir (notably not amprenavir) induced endoplasmic reticulum dysfunction in the intestinal epithelial cells [36]. When exposed to protease inhibitors, the cells were found to have decreased alkaline phosphatase activity and thereby an increase in unfolded proteins. The accumulation of defective proteins in the cytosol may persistently activate the cell’s unfolded protein response, a specific signaling pathway that aims to return the cell’s protein folding function back to normal. If the levels of unfolded proteins do not decrease, the cell may induce apoptosis.

Table 2 Incidence of ART-associated diarrhea [32]
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Other Causes of Noninfectious Diarrhea

Functional bowel disorders, such as irritable bowel syndrome (IBS), are additional conditions that may present with diarrhea [8]. In a survey conducted in a Veterans Affairs outpatient setting, IBS was more common in HIV-positive patients compared with HIV-negative patients [37]. Another cause of noninfectious diarrhea is small intestinal bacterial overgrowth (SIBO) [38], a condition in which increased bacteria in the small intestine leads to multiple GI symptoms, including abdominal bloating and discomfort, diarrhea, and malabsorption [39]. This condition may be more common in those with anatomic abnormalities and motility disorders, but does not appear to be a common cause of diarrhea in those with HIV [40].

Infectious Etiologies of Diarrhea

Given the multitude of differences in standard of living among developed versus developing countries and differences in availability of care for patients with HIV, the incidence and type of various diarrhea-associated infections in immunocompromised patients may vary substantially by region [41, 42]. In addition, diarrhea experienced by HIV-infected individuals can be caused by pathogens that are unique to the HIV population or by pathogens that cause diarrhea in the immunocompetent host [41, 43]. For example, Salmonella, Shigella, Campylobacter, Escherichia coli, and enterotropic viruses cause diarrhea in both the immunocompetent and HIV-infected patients. In addition to these pathogens, patients with HIV who are profoundly immunosuppressed, with a CD4+ T cell count <200 cells/mm3, are also susceptible to opportunistic infections [44]. These opportunistic infections can be organized into four general categories of organisms: protozoa, fungi, viruses, and bacteria (Table 3) [41, 45–48].

Table 3 Infectious causes of diarrhea in patients with HIV diagnosed by endoscopy or colonoscopy [41, 45–48]
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Protozoa

Cryptosporidiosis is caused by an intracellular pathogen, Cryptosporidium [49]. Infection with Cryptosporidium parvum is a common cause of diarrhea worldwide [45]. There is an estimated rate of ~60,000 cases of cryptosporidial infection per year in the USA [50]; risk of Cryptosporidium parvum infection is greater in developing countries where there is poor sanitation [51–53]. It spreads from person to person or via contaminated water (e.g., drinking water or recreational water sites) [54]. Although the protozoa cause a mild, self-limited disease in immunocompetent individuals, it can manifest as severe, watery diarrhea in HIV-infected patients and it can also occasionally lead to a chronic infection [49]. In the profoundly immunocompromised, Cryptosporidium parvum can lead to a malabsorptive syndrome, severe dehydration, and electrolyte derangements [49, 55].

Other protozoal infections that commonly affect patients with HIV include Microsporidia, Isospora, Cyclospora, and, less commonly, Toxoplasma and Leishmania species, which like Cryptosporidium, affect the small intestine and can lead to malabsorptive diarrheal illnesses [41]. Similarly, Giardia also is a very common protozoal pathogen in both HIV-infected and immunocompetent hosts and infects the small intestinal mucosa. Entamoeba histolytica is a protozoal pathogen that can cause colitis in the severely immunocompromised HIV-infected patient and in rare and severe circumstances can lead to ulceration, hematochezia, and even toxic megacolon.

Viruses

Cytomegalovirus (CMV) is the most common viral GI pathogen in patients with AIDS [44]. CMV can affect the entire GI tract but classically leads to diarrhea by causing colitis characterized by rectal bleeding, abdominal pain, and systemic signs such as fevers and weight loss [55]. HIV infection itself can cause a diarrheal illness as described below, and multiple other viruses have been implicated as diarrheal pathogens, including adenovirus, coronavirus, herpes simplex virus, rotavirus, and norovirus [44, 46].

Fungi

Rarely have fungi been reported to cause diarrhea in HIV-infected patients [44]. Of the infections associated with endemic fungi, histoplasmosis is the most common fungal infection requiring hospitalization and can affect any part of the GI tract, causing diarrhea, weight loss, and fever [56].

Bacteria

Mycobacterium avium complex (MAC) typically causes diarrhea in patients with AIDS with profoundly suppressed immune systems (i.e., CD4+ T cell count <50 cells/mm3) [44]. Symptoms are varied, but they usually reflect the systemic nature of the disseminated infection and include fever and weight loss [45]. MAC usually involves the small intestine; however, it can affect the entire GI tract [55, 57].

Salmonella, Shigella, Campylobacter, and E coli are bacterial infections of the GI tract that can present with diarrhea [41]. They are usually spread through food and water contamination. Patients with an impaired immune system can become asymptomatic carriers of some pathogens (e.g., Shigella, Campylobacter). Clostridium difficile should be investigated in patients who have recently taken antibiotics [47]. It causes pseudomembranous colitis that can progress to toxic megacolon in severe infections. Clostridium difficile is more common in patients with advanced AIDS (CD4+ T cell count <50 cells/mm3). In one study evaluating the incidence of bacterial diarrhea in patients with HIV, Clostridium difficile was the most common identified culprit, accounting for 53.6 % of 1115 episodes of diarrhea that had a bacterial pathogen isolated [36].

Overall, protozoa, fungi, MAC, and CMV GI infections are usually seen only in patients with HIV and other immunocompromised patients [58]. As noted earlier, with improved therapy, patients infected with HIV are less prone to develop diarrhea due to infectious pathogens and are more prone to noninfectious causes [48].

Diagnosis

The basic algorithm for the diagnosis and evaluation of diarrhea in patients with HIV is similar to the examination of diarrhea in the immunocompetent host and starts with a thorough medical history [55]. This includes the duration of the diarrhea, constitutional and systemic symptoms, the presence or severity of abdominal pain, and questions on the characteristics of diarrhea (e.g., large versus small volume; infrequent or nocturnal versus frequent) to help localize the source to the large or small intestine and narrow the differential diagnosis (Fig. 2) [8, 55]. Classically, diarrhea from pathology in the small intestine presents as voluminous and watery, occasionally associated with weight loss as well as signs and symptoms of malabsorption [59]. Bloating, nausea, and cramping may also indicate a small intestine source. Diarrhea from the large intestine is typically characterized by smaller, more frequent bowel movements [48]. If there is inflammation of the rectum and anus, patients may describe tenesmus and painful defecation, which may be associated with hematochezia. A careful review of medications, travel history, contact with ill individuals, recent ingestions, family history, surgical history, and social history is important in evaluating acute and chronic diarrhea in the patient infected with HIV [8].

Fig. 2
figure 2

General algorithm for the diagnosis and management of diarrhea in patients with HIV. ART antiretroviral therapy, HIV human immunodeficiency virus. Reprinted with permission from [8]

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Physical examination and medical history of a patient with HIV and diarrhea may help to evaluate the chronicity of the diarrhea and the severity of illness and thereby focus the differential diagnosis. Nutritional status should be assessed by evaluating for bitemporal wasting, weight changes, skin turgor, and mucosal dehydration. Basic vital signs and orthostatic vital signs are essential to gauge the severity of the patient’s illness and the degree of the patient’s volume depletion. Documented fever may be an important clue of an infectious etiology, though the absence of fever in an immunocompromised host does not rule out the possibility of an infection. The GI examination may reveal tenderness to palpation, possibly indicative of pancreatic pathology or colitis. Hepatosplenomegaly may represent mycobacterial infection, hepatitis, or fungal or malignant causes of diarrhea. A rectal examination is of integral importance because it may reveal signs of sexually transmitted infections, bleeding, tenderness, and masses, all of which may help to establish a diagnosis. A careful, comprehensive examination of the patient is essential to evaluate the severity of disease, narrow the diagnosis, and guide the management.

Further diagnostic evaluation may also aid in a diagnosis [8]. Laboratory tests should include comprehensive metabolic panel, complete blood count with cell differential, blood cultures, HIV viral load, and CD4+ T cell count to gauge the level of immune suppression. Stool examinations should include fecal lactoferrin, fecal leukocytes, fecal calprotectin, fecal occult blood, and Clostridium difficile stool culture, as well as three separate samples of ova and parasites. Infection with Cryptosporidium parvum is most commonly diagnosed by microscopic identification or enzyme immunoassay of the organisms in the stool of patients but can also be made by biopsy of the GI tract or aspiration from the biliary tree during endoscopy. Diagnosis of Giardia can be made by immunoassay of the stool but, again, can be identified on endoscopic biopsy or on luminal aspiration during endoscopy. Diagnosis of bacterial infections of the GI tract, such as Salmonella, is made by stool culture.

If no pathogen is identified, further workup is needed with an endoscopic examination [8]. Colonoscopy with biopsy is necessary for diagnosis of CMV and HSV and may reveal hemorrhage, colitis, and ulcers [46]. There is some debate as to whether sigmoidoscopy or full colonoscopy would be beneficial; one colonoscopy study (n = 44) showed that nearly 40 % of 18 patients with CMV-associated colitis had disease localized to the cecum [60]. However, a prospective study comparing sigmoidoscopy and full colonoscopy showed that the sensitivity of a sigmoidoscopy was 77 % for enteric pathogens and full colonoscopy only yielded a small increase in sensitivity to 82 %, with no additional cases of CMV-associated colitis identified [61]. Diagnosis of MAC infection within the GI tract requires endoscopy, which may identify ulcerations, erythema, or normal mucosa but may also reveal foamy macrophages and positive culture via biopsy [45]. Diagnosis of fungal infections may be made histologically from biopsies taken for endoscopy or colonoscopy [58]. Mucosal biopsy can also help diagnose inflammatory bowel disease. For patients with negative diagnostic results, the diagnosis of noninfectious diarrhea can be made.

Treatment

The treatment of infectious diarrhea is outside the scope of this article, and this section will focus on the treatment of noninfectious diarrhea. If no other cause of diarrhea is identified, patient medications should be reviewed to evaluate for an iatrogenic cause of the diarrhea. Pharmacologic options for the treatment of noninfectious diarrhea in patients with HIV are primarily supportive. Hydration via intravenous and oral routes, repletion of electrolytes, and treating the underlying cause, if possible, are important therapies for any patient with diarrhea [62]. Noninfectious diarrhea can be managed by modifying ART and controlling symptoms with medications and lifestyle modification. However, clinical guidelines for patients with HIV recommend careful evaluation of the symptoms and symptomatic management of ART-related AEs (e.g., diarrhea) before switching ART, with supportive care (e.g., antidiarrheals) generally allowing for continuation of prescribed ART therapy [63, 64]. However, cessation of ART (“drug holiday”) is generally not advised as a management strategy.

Antidiarrheal medications used in noninfectious diarrhea can be divided into several classes: adsorbents, antimotility agents, and antisecretory agents (Table 4) [8, 32, 62, 65–71]. Adsorbent drugs bind bacterial toxins, fluids, and other compounds in the intestines to improve stool consistency [65]. Drugs in this category include bismuth subsalicylate, kaolin/pectin, and attapulgite (aluminum magnesium silicate purified from clay). Data on the use of adsorbents in patients with HIV are limited to one study in which the efficacy of attapulgite was not better than placebo in the management of diarrhea [65, 72].

Table 4 Pharmacologic treatment of noninfectious diarrhea in patients with HIV [8, 32, 62, 65–71]
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Antimotility agents include loperamide, diphenoxylate/atropine, and tincture of opium [65]. These agents act upon opioid receptors in the gut to slow motility by decreasing peristalsis and increasing tone in the large intestine. This allows for greater fecal transit time and therefore longer time for water absorption.

The antimotility agent diphenoxylate crosses the blood–brain barrier and can cause central effects analogous to other opioid agonists [62]. To prevent the abuse of diphenoxylate, it is usually sold as a combination agent with atropine. Loperamide does not cross the blood–brain barrier and does not have these adverse effects. One disadvantage to loperamide is that it may interact with ART agents, such as ritonavir and saquinavir, which can limit its use for long-term therapy [62, 67]. However, loperamide has been shown in a small trial to decrease the number of bowel movements in patients with protease inhibitor-induced diarrhea [73]. The use of the combination of low-dose diphenoxylate/atropine may be efficacious for treating protease inhibitor-induced diarrhea; however, it appears that this combination had no beneficial effect in patients who were refractory to loperamide therapy [66]. Although not studied for the treatment of diarrhea in patients with HIV, tincture of opium is considered more effective than loperamide as an antimotility agent, and it can be titrated easily. Tincture of opium may be considered early in the treatment algorithm for patients with severe HIV-associated diarrhea.

Antisecretory agents, such as octreotide, racecadotril, and crofelemer, directly inhibit secretory processes within enterocytes [62, 68–71]. The mechanism of action of octreotide, administered subcutaneously, is unclear, but it is believed to alter the binding of vasoactive intestinal peptide, therefore acting as an antimotility and antisecretory agent [8, 62, 74]. Published data conflict about the efficacy of octreotide in treating diarrhea in patients with AIDS [75, 76]. Oral racecadotril is an enkephalinase inhibitor, which decreases the breakdown of endogenous gut opioids, thereby decreasing the secretion of water and electrolytes into the gut lumen [69]. Racecadotril is not currently available in the USA.

Orally administered crofelemer is a dual inhibitor of cAMP-stimulated cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-stimulated calcium-activated chloride channels (CaCC) in the gut [77]. Crofelemer is a minimally absorbed GI drug derived from the latex of the Croton lechleri tree, and has reportedly been used by Amazonian tribes for diarrheal relief [68]. Crofelemer is the only agent approved in the USA for the symptomatic relief of noninfectious diarrhea in patients with HIV on ART [78]. Compared with placebo, crofelemer has been shown, in a randomized, double-blind, placebo-controlled trial with an open-label extension, to significantly reduce symptoms of noninfectious diarrhea in patients with HIV receiving ART (percentage of patients with ≤2 watery stools per week for at least 2 of 4 weeks during placebo-controlled phase: 17.6 versus 8.0 %, respectively; P = 0.01) [70]. In addition, crofelemer has no known drug interactions with ART drugs, is minimally absorbed, and does not have a negative impact on the clinical immune parameters (e.g., HIV viral load and CD4+ T cell counts) [68, 70, 71].

Conclusions

Diarrhea is a common complication of HIV infection that has substantial clinical ramifications. The differential diagnosis for diarrhea in patients with HIV is broad. While infection has historically been the major cause of diarrhea in patients with HIV, with the widespread use of ART therapy, noninfectious diarrhea has become a burden in this population. Medications used for noninfectious diarrhea include antimotility and antisecretory agents, including crofelemer, which has been shown to significantly reduce symptoms of noninfectious diarrhea. Improved treatment of noninfectious diarrhea will likely improve HIV medication adherence and quality of life.