The stage of immunodeficiency, reflected by the CD4 lymphocyte count, should be kept in mind when approaching any HIV-infected patient with GI symptoms because the etiology and the frequency of opportunistic infections are related to the CD4 count and rises exponentially if CD4 is < 100 cell/ul.

The upper GI tract is a topographical target of HIV infection. Candida is the most common oesophageal pathogen in AIDS. However, in the era of antiretroviral therapy (ART), many of the previously common HIV-related disorders are vanished [6], but they can be observed in patients who are failing on HAART or non-adherent to therapy [7]. The approach to HIV patients with a CD4 count > 200 cell/μl and upper GI symptoms should parallel that of any other non-HIV-infected subject. Upper endoscopy remains the gold standard diagnostic approach in case of suspected gastro-oesophageal reflux disease, dysphagia or bleeding. In severely immunosuppressed children, in whom opportunistic infections are considered, upper endoscopy with multiple tissue sampling should be performed for a definitive diagnosis [8]. For example, multiple biopsies (about 10) increase the yield for cytomegalovirus (CMV) disease [9].

Intestinal infections are a major cause of morbidity and mortality, especially for children, and where the availability of HAART is limited. In patients with advanced HIV disease, opportunistic infections are the most common cause of disease. Cryptosporidium and microsporidium are the most common pathogens in developing countries and CMV in developed world. However, although opportunistic causes of diarrhea have fallen dramatically in the era of ART, overall the number of patients experiencing diarrhea has changed very little [10]. Other infections unrelated to immunodeficiency and noninfectious causes are also increased in HIV-infected children. Drug-induced diarrhea is an important cause of diarrhea in HIV patients [11]. Severe diarrhea associated with villous atrophy and crypt hypertrophy with no pathogen is found despite extensive investigation is defined as HIV enteropathy. The approach to diarrhea in HIV-infected patients should be based on routine stool testing, but these are often repeatedly negative, mainly in severe immunosuppressed subjects. In these cases, endoscopic examination with biopsy is able to establish a diagnosis in 65–80 % of cases [8].

Intestinal dysfunction is a specific HIV-related syndrome in children [3]. The clinical manifestations of intestinal dysfunction may be limited or absent. Namely dysfunction is not consistently associated with diarrhea but its most prominent features are steatorrhoea, reduction of the intestinal absorptive surface and increased permeability [3]. Despite the limited or absent clinical manifestations of intestinal dysfunction, nutrient malabsorption certainly contributes to weight loss, and its clinical consequences may be expected in the long term and associated with progressive failure to thrive. The pathophysiology of intestinal dysfunction is complex and involves multiple abnormalities. HAART is able to restore intestinal function tests in HIV-infected children, in parallel with a decrease in viral load and an increase in CD4 T cell count [3]. This suggests that in case of malnutrition in a child receiving ART, careful monitoring of antiretroviral therapeutic efficacy is needed, as malnutrition may be an early marker of treatment failure.

Liver disease is the second most common cause of death among adults with HIV infection. Just as the burden of non-AIDS morbidity and mortality has changed in the ART era, the spectrum of liver diseases has also changed in these patients [12]. Prior to ART, the most common causes of liver dysfunction were opportunistic infections , including CMV and mycobacterium infections, AIDS lymphoma and Kaposi’s sarcoma. Since the HAART era, however, the spectrum of liver disease among HIV-infected individuals has shifted to concomitant infection with chronic hepatitis C virus (HCV), and chronic hepatitis B virus infections, medication-related hepatotoxicity and nonalcoholic fatty liver disease (NAFLD) . Although hepatic dysfunction is not frequent in HIV in children, hepatomegaly without other symptoms of systemic disease is commonly found in pediatric patients, and it is often associated with nutritional deficiency. HBV and HCV infections may be more severe in HIV-infected children than in HIV-negative individuals. In addition, liver toxicity is one of the most common serious adverse events associated with ART [12].

Pancreatic dysfunction may be considered as a component of HIV-associated digestive dysfunction in HIV. In fact, a reduction of faecal levels of pancreatic elastase and/or chymotrypsin has been found in one third of HIV-infected children [13]. The clinical manifestations of pancreatic involvement may not be evident, because exocrine, rather than endocrine pancreatic function, is involved. Pancreatitis may be an unusual but serious drug adverse effect, mainly with selected nucleoside analogue reverse transcriptase inhibitors.

Since the discovery of HIV as an agent of AIDS , histological abnormalities of GI tract were observed, and the term “HIV enteropathy” was firstly used in 1984 [14] . Many investigators found that HIV itself infected enterocytes, lamina propria and submucosal cells. The enteropathy was characterized by inflammatory infiltrates of lymphocytes, damage to the GI epithelium, villous atrophy, crypt hyperplasia, and villous blunting, in the absence of detectable enteropathogens, recurring in all stages of HIV disease [15]. GI abnormalities associated with HIV infection include a decreased capacity for epithelial regeneration, impaired absorptive ability of GI mucosa, increased mucosal permeability, dysregulations of genes associated with T cell homeostasis, decreased growth factor production and cell-cycle mediators and upregulation of genes associated with apoptosis [16–18] .

Not surprisingly, inflammatory changes are mild or absent. Once opportunistic disorders are excluded in patients with refractory diarrhea, HIV enteropathy is diagnosed in a small but definite percentage of patients. The HIV enteropathy encompasses an idiopathic, pathogen-negative diarrhea, and it can occur from the acute phase of the HIV infection through advanced disease, leading to GI inflammation, increased intestinal permeability, bile acid and vitamins malabsorption [19]. The functional disruption of the GI caused by HIV has been reported also in the absence of clear clinical GI manifestations in the era of modern ART [20]. More than one third of HIV-infected patients present an abnormal D-xylose test, about 20 % has low or borderline serum B12 levels and 7 % has low albumin levels, in the absence of stool pathogens [20].

Although the mechanisms responsible for these abnormalities remain not completely known, several explanations have been put forward, from a virotoxic effect of HIV itself on enterocytes [21, 22] to an abnormal differentiation of enterocytes induced by HIV [23, 24], to local activation of the GI immune system [25]. However, a major role is likely associated with HIV transactivator factor (Tat) [21] .

Immunopathogenesis of HIV involves two phenomenons: the loss of lymphoid cells and the loss of immune function. Several pathological changes, both structural and immunological, occur at the intestinal mucosal surface from the initial stage of HIV infection. The intestinal mucosa is a target for HIV and a site of significant HIV replication and CD4 T cell destruction, based upon the route of exposure and other aspects of mucosal immunology [26, 27]. Gut-associated lymphoid tissue (GALT) was identified as an early site of HIV replication and CD4 T cells depletion since the initial stage of HIV infection [28]. Even with early and aggressive HAART, GALT is not preserved and undergoes significant damage.

The sensitivity by intestinal tract to HIV infection relates in part to the high number of activated memory T cells expressing C-C chemokine receptor type 5 (CCR5) chemokine receptors located within the gut. HIV-1 isolated from acutely infected subjects are predominantly R5 viruses, that is macrophage-tropic HIV that requires CCR5 for cell entry, in contrast to R4 virus, lymphocyte-tropic HIV requiring the C-X-C chemokine receptor type 4 (CXCR4) chemokine receptor [29]. The preferential loss of CCR5 + CD4 T cells from the GI tract clearly suggests a virus-centric mechanism. Furthermore, the intestinal mucosa has continuous exposure to antigens, leading to a pro-inflammatory state, and secretes many cytokines that stimulate HIV replication [18].

There is a compartimentalization of HIV infection between blood and mucosa, mainly due to viral factors. The CD4/CD8 ratio was analysed in the duodenum and peripheral blood in order to compare CD4 T cell depletion between these two anatomical sites, and it was found that the GI tract was preferentially depleted of CD4 T cells [30–33]. Moreover, CD4 T cells in the GI tract are tenfold more frequently infected by HIV than those in the peripheral blood, suggesting that the viral reservoir in the intestine is much greater than previously thought [34].

Another mechanism that can contribute to the HIV enteropathy is the infection of enterocytes by HIV 1. In in vitro experiments, HIV is able to replicate in the intestinal epithelial cell lines [35, 36]. However, virus-direct and -indirect effects have been described. In addition to structural and enzymatic proteins, HIV-1 encodes a group of at least six auxiliary regulatory proteins, including Tat , a transactivating peptide essential for HIV replication, which exerts its effects by activating L-type Ca²⁺ channels, and/or mobilizing intracellular calcium stores [37, 38]. Tat is secreted from HIV-1-infected cells and is taken up by neighbouring uninfected cells. In vitro experiments using human colonic adenocarcinoma (caco-2) cell monolayers and human colonic mucosa specimens mounted in ussing chambers, it has been shown that Tat protein induced ion secretion similar to that induced by bacterial endotoxins. It also significantly prevents enterocytes proliferation [39]. On the bases of these data, it is likely that Tat directly exerts pathogenic effects on enterocytes and is involved in the pathogenesis of intestinal mucosal atrophy typical of HIV-infected patients, that is, in HIV enteropathy .

Tat has been implicated also in enterocyte apoptosis. Tat causes an imbalance in reactive oxygen species (ROS) generation in neurons, which is neutralized by antioxidants, thereby implicating perturbation of the intracellular redox status in the pathogenesis of HIV-induced cell damage [40]. Oxidative stress is implicated in the pathogenesis and morbidity of HIV infection. An increase of ROS and an alteration of antioxidant defences have been reported in HIV-infected patients [41] associated with decreased levels of antioxidants [42]. The mechanisms involved in HIV-induced oxidative stress are unknown, but HIV-1 proteins gp120 and Tat have been implicated in this process because they both induce oxidative stress and cause apoptosis in brain endothelial cells [43]. Similar mechanism has been involved in intestinal mucosa (Fig. 18.2). In an in vitro cell model, Tat increased the generation of ROS and decreased antioxidant defences as judged by a reduction in catalase activity and a reduced glutathione (GSH)/oxidized glutathione disulfide (GSSG) ratio [44]. Tat also induces cytochrome c release from mitochondria to cytosol, and caspase-3 activation. Rectal dialysis samples from HIV-infected patients were positive for the oxidative stress marker 8-hydroxy-29-deoxyguanosine. GSH/GSSG imbalance and apoptosis were observed in jejunal specimens from HIV-positive patients at baseline and from HIV-negative specimens exposed to Tat. Experiments with neutralizing anti-Tat antibodies showed that these effects were direct and specific. Pretreatment with N-acetyl cysteine (NAC) prevented Tat-induced apoptosis and restored the glutathione balance in both the in vitro and the ex vivo model [44]. These findings indicate that oxidative stress is one of the mechanism involved in HIV intestinal disease (Fig. 18.3).

HAART reduces viral loads and increases CD4 T cells. GI symptoms including abdominal pain , bloating and diarrhea improve after initiation of treatment, in parallel with CD4 T cell reconstitution in blood and a decrease in viral load in rectal tissue [36]. The effects of HAART on intestinal CD4 T cells are lower than in peripheral blood [45, 46]. Furthermore, HAART started early during infection leads to an increase in CD4 central memory cells in Peyer’s patches , but does not restore effector memory cells in the ileal lamina propria [47, 48]. Initiation of HAART during chronic infection does not significantly increase CD4 T cells in gut-inductive or -effector sites [45, 46]. Finally, no HIV-infected individual reconstituted GI tract CD4 T cells to levels observed in uninfected persons. These findings suggest that fibrotic damage severely disrupt the ability of GALT to support normal T cell trafficking and survival, even after HAART onset. In addition, not only CD4 T cells fail to fully repopulate the GI tract following HAART but also HIV proviral DNA persists in CD4 T cells in terminal ileum 10 years after effective therapy [49]. As a consequence, viral replication persists at low levels in the intestine despite HAART .