Insights into gastrointestinal manifestation of human immunodeficiency virus: A narrative review

Abstract

Human immunodeficiency virus (HIV) modifies CD4-positive cells, resulting in immunodeficiency and a wide range of gastrointestinal (GI) manifestations. The burden of HIV-related GI illnesses has significantly evolved with the widespread use of antiretroviral therapy (ART). While ART has effectively reduced the occurrence of opportunistic infections, it has led to an increase in therapy-related GI illnesses. Common esophageal conditions in HIV patients include gastroesophageal reflux disease, idiopathic esophageal ulcers, herpes simplex virus, cytomegalovirus (CMV), and candidal esophagitis. Kaposi’s sarcoma, a hallmark of acquired immunodeficiency syndrome, may affect the entire GI system. Gastritis and peptic ulcer disease are also frequently seen in patients with HIV. Diarrhea, often linked to both opportunistic infections and ART, requires careful evaluation. Bloody diarrhea, often a sign of colitis caused by bacterial infections such as Shigella or Clostridium difficile, is prevalent. Small bowel lymphoma, although rare, is increasing in prevalence. Anorectal disorders, including proctitis, fissures, and anal squamous cell carcinoma, are particularly relevant in homosexual men, underlining the importance of timely diagnosis. This review comprehensively explores the epidemiology, pathogenesis, and treatment considerations for the various GI disorders associated with HIV, highlighting the importance of accurate diagnosis and effective treatment to improve outcomes for HIV-infected patients.

Key Words: Human immunodeficiency virus; Opportunistic infections; Antiretroviral treatment; Gastrointestinal

Core Tip: Human immunodeficiency virus (HIV) modifies CD4-positive cells, causing immunodeficiency and leading to various gastrointestinal (GI) issues. Highly active antiretroviral therapy (ART) has shifted the burden of HIV-related GI illnesses, reducing opportunistic infections while increasing GI problems associated with therapy, such as gastroesophageal reflux disease, non-infectious diarrhea, and HIV enteropathy. Diarrhea, linked to both infections and ART, requires careful evaluation to identify the etiology. Conditions such as colitis-related bloody diarrhea, small bowel lymphoma, and anorectal disorders, including proctitis and anal squamous cell carcinoma, also require timely diagnosis and management, especially in at-risk populations.

INTRODUCTION

The epidemiology of human immunodeficiency virus (HIV) has changed significantly over the past few decades, particularly with the introduction and widespread adoption of active antiretroviral therapy (ART). As of 2017, an estimated 36.8 million people worldwide were living with HIV, with the highest prevalence in southern sub-Saharan Africa. The incidence of new HIV cases peaked in 1999 at 3.16 million but decreased to 1.94 million by 2017. Similarly, HIV-related mortality reached its highest point in 2006 with 1.95 million deaths, dropping to 0.95 million deaths by 2017[1]. HIV interacts with host cells that express the CD4 surface glycoprotein in order to be recognized, making CD4-expressing T cells and macrophages the main targets of the virus. The envelope glycoprotein on the viral surface facilitates viral entry into host cells. Chemokine coreceptors, CCR5 and CXCR4, present on the host cell surface, induce a conformational change in the envelope protein, resulting in the fusion of viral and host cell membranes. This membrane fusion releases the viral capsid into the host cell. HIV manipulates these CD4-positive cells to facilitate its multiplication, resulting in their elimination, disruption of T cell homeostasis, and subsequent immunodeficiency[2].

Multiple opportunistic infections and some cancers are characteristics of AIDS that clearly define it as a disease based on cell-mediated immunity. HIV can cause a wide range of conditions in the gastrointestinal (GI) tract, leading to symptoms ranging from dysphagia to bloody diarrhea and tenesmus. GI problems are quite prevalent in HIV patients and might result from immunosuppressed states that make them more vulnerable to opportunistic infections, medication-induced consequences, or other underlying etiologies. It has been suggested that more than 70% of the patients will have GI manifestations during their disease course[3]. HIV-related GI disorders have changed significantly since the mid-1990s with the introduction of highly ART. As of now, 50%-70% of HIV patients reported GI symptoms. With the increased use of ART, the prevalence of opportunistic infections has declined, changing the burden of GI diseases in HIV patients.

In addition to the increased risk of infections, HIV may also lead to the development of tumors secondary to immunosuppression. HIV-associated neoplasms and infections are the two primary categories of these GI illnesses. Squamous cell carcinoma, non-Hodgkin's lymphoma, and Kaposi sarcoma (KS) are examples of HIV-acquired neoplasms, while common infections include ailments like cytomegalovirus and tuberculosis (TB)[4,5]. The presentation of these disorders varies significantly leading to much diagnostic confusion. Anorectal disorders are also common, which may present as tumors, warts, ulcers, and infections in the anorectal area[6]. The complex link between HIV infection and GI diseases is highlighted by these clinical problems, underscoring the need for a thorough knowledge of these manifestations to effectively treat patients and improve their quality of life.

To diagnose the underlying illness and provide the right medication, HIV patients who appear with GI problems must be evaluated using a comprehensive strategy that includes a full medical history, a thorough physical examination, and targeted diagnostic testing[3]. This review aims to provide insight into the dynamic nature of HIV-related GI illnesses and the critical role that contemporary diagnostic and treatment approaches play in the management of this condition.

The objective of conducting this literature review was to assess the various GI manifestations noted in HIV patients. Various databases, including PubMed, Google Scholar, EMBASE and MEDLINE, were used (from Inception to May 2024) to locate sources for this literary analysis. Search terms used for this review included “HIV” “gastrointestinal manifestations” “antiretroviral therapy” “opportunistic infections” “esophagitis” “Kaposi’s sarcoma” and “diarrhea”. The studies were reviewed by two independent authors (Moliya P and Singh A), and if there was any conflict regarding the inclusion/exclusion of the study in the literature review, the opinion of the third author (Sohal A) was taken into account. Studies were included if they focused on GI disorders in HIV patients and were published in English. Exclusion criteria were studies not focusing on HIV-associated GI conditions or those with incomplete data. To minimize selection bias, studies were evaluated based on their relevance, quality, and recency.

ESOPHAGEAL MANIFESTATIONS IN HIV

Patients with HIV/acquired immunodeficiency syndrome (AIDS) often exhibit various upper GI symptoms, ranging from odynophagia (discomfort on swallowing) to dysphagia (trouble swallowing). Opportunistic infections are more prevalent in HIV patients with low CD4 counts and the severity of the symptoms is directly correlated with CD4 count. The most common opportunistic manifestations in the esophagus include Herpes simplex virus (HSV), cytomegalovirus (CMV), and Candida species[7]. Additionally, HIV patients may also be affected by a disorder called idiopathic esophageal ulcers (IEU), which may be brought on by immunological factors or direct consequences of HIV. Non-infectious conditions and malignancies such as lymphoma and Kaposi's sarcoma are also possible manifestations. Before the advent of ART, the burden of esophageal manifestations secondary to opportunistic infections was high. However, after the advent of ART and protease inhibitors (PIs) in 1996, there has been an observed increase in esophageal conditions such as gastroesophageal reflux disease (GERD), Pill esophagitis, etc. in this patient population[8].

While odynophagia is usually a sign of esophageal ulcerative illness, dysphagia is often linked to candidal esophagitis[9]. Considering that some patients with HIV may have both odynophagia and dysphagia, a thorough evaluation is essential (Figure 1, Table 1).

Figure 1 Clinical strategy for management of human immunodeficiency virus positive patients presenting with complaints of dysphagia and odynophagia. EGD: Esophagogastroduodenoscopy.

Table 1 Various esophageal manifestations in patients with human immunodeficiency virus.

Type	CD4 counts	Endoscopic findings	Biopsy findings	First line therapy	Alternative treatment(s)
Candidal esophagitis	< 200/uL	White plaques, exudates, mucosal lesions	Yeast with pseudohyphae, parakeratosis	Fluconazole: 200 mg loading dose, followed by 100 mg daily for 10-14 days	Isavuconazole: (200 mg load, then 50 mg daily; 400 mg load, then 100 mg daily; or 400 mg weekly), posaconazole for refractory cases (400 mg twice daily for 28 days)
CMV esophagitis	< 50/uL	Well-demarcated vertical ulcers, single or multiple	Intracellular: Inclusions with clear halo- “owl's eye" appearance	Ganciclovir: 10-15 mg/kg daily in divided doses for 3-6 weeks	Valganciclovir (oral), foscarnet for resistance, combination therapy with ganciclovir and foscarnet in case of failure
HSV esophagitis	< 200/uL	Fragile mucosa with distinct vesicles and “volcano” ulcers	Multinucleated giant cells, cowdry a inclusion bodies	Acyclovir 200 mg five times a day or 400 mg three times a day for 7-10 days	Famciclovir, valacyclovir
Idiopathic esophageal ulcers		Large single ulcers, profound depth, located mid-esophagus	Negative for infections or malignancy	Oral steroids dosages vary based on severity and patient response	Thalidomide (as a therapeutic trial in severe cases)
Pill esophagitis		Varied ulcerations along the esophageal lining	Granulation tissue, necrotic squamous epithelium, and intraepithelial eosinophils	Behavioral changes like taking medication with enough water, avoiding lying down immediately after taking pills	Prevention is key; treatment focuses on behavioral changes)

Candidal esophagitis

The most frequent cause of esophagitis in HIV patients is candidal esophagitis with the prevalence of Candidal esophagitis being 11.2% in HIV-infected patients while 2.9% in non-HIV-infected patients[10]. Although other Candida species may potentially infect the esophagus, Candida albicans are often the culprit, accounting for 88% of cases. Patients who have esophageal symptoms, particularly dysphagia, odynophagia, and retrosternal pain with a CD4+ lymphocyte count of less than 100 cells/μL, should be suspected of having this condition. Systemic antifungals like Fluconazole are useful empirical therapy with 82% of patients showing improvement[11]. Fluconazole is taken orally in loading doses of 200 mg and then 100 mg every day for a period of 10 to 14 days[12]. A two-week regimen of isavuconazole, administered orally, is as effective as fluconazole for treating uncomplicated esophageal candidiasis. This regimen includes options for a loading dose of 200 mg followed by 50 mg daily, a loading dose of 400 mg followed by 100 mg daily, or 400 mg weekly[13]. However, patients with severe dysphagia may face challenges swallowing oral drugs.

While symptoms of esophageal candidiasis can be mimicked by infections such as CMV or HSV esophagitis, initiating antifungal therapy is generally recommended as both a diagnostic and therapeutic approach before considering endoscopy. If there is no response to the antifungal treatment, endoscopy is recommended to investigate other causes of esophagitis or drug-resistant Candida (Figure 1). Most patients respond quickly to antifungal therapy; signs and symptoms typically improve within 48 to 72 hours. The refractory disease affects around 4% to 5% of HIV-positive patients with esophageal candidiasis, particularly those with CD4 counts below 50 cells/mm³ and extensive azole treatment history. For such cases, Posaconazole oral suspension (400 mg twice daily for 28 days) is effective in 75% of patients. Alternatives include anidulafungin, caspofungin, micafungin, or voriconazole for azole-refractory esophageal candidiasis[14].

CMV esophagitis

CMV is the most frequent viral opportunistic infection in individuals with AIDS, with the esophagus being the second most commonly affected site in the GI tract after the colon. Patients are most vulnerable to opportunistic infections when their CD4+ T lymphocyte cell count falls below 50 cells/mm³[15]. Dysphagia and odynophagia are symptoms associated with CMV esophagitis. Endoscopy and biopsy are the gold standard for diagnosing the condition, which might reveal well-demarcated, vertical, single, or multiple ulcers or widespread esophagitis at the mid to distal esophagus. The primary treatments for CMV esophagitis are ganciclovir and valganciclovir. Treatment begins with induction therapy using intravenous ganciclovir at 10-15 mg/kg daily in divided doses for 3 to 6 weeks, depending on the patient's condition. Maintenance therapy involves daily intravenous ganciclovir at 5 mg/kg, particularly for those with concurrent retinitis or recurring symptoms. Relapse is common due to underlying severe immune deficiency, and treatment suppresses rather than eradicates the virus. If resistance develops, foscarnet is an alternative, and in patients with monotherapy, combination therapy with ganciclovir and foscarnet is beneficial[16]. CMV esophagitis in immunocompromised patients is associated with considerable morbidity and mortality, with some studies indicating up to a 25% mortality rate within one year[17].

HSV esophagitis

HSV esophagitis mostly occurs in immunocompromised hosts, particularly HIV patients, and it mostly co-exists with herpes labialis or oropharyngeal ulcers; it is rare in immunocompetent patients. Most cases of HSV esophagitis typically occur at an average age of 35 years, mainly in males, and are caused by HSV-1, though a few cases of HSV-2 esophagitis have also been reported[18]. HSV esophagitis may present either as a primary infection or as a reactivation, typically featuring acute systemic symptoms and widespread erosive-ulcerative lesions in the mid to distal esophagus. Patients often experience an initial prodrome of systemic symptoms such as fever, nausea, or vomiting, which precedes the onset of esophageal symptoms. The GI manifestations commonly include odynophagia, dysphagia, heartburn, epigastric pain, and occasionally atypical symptoms such as chest pain.

HSV esophagitis is typically identified through endoscopic findings, with further confirmation from histopathology. Endoscopically, it appears as fragile mucosa dotted with distinct vesicles and “volcano” ulcers, usually 1-3 mm in size, predominantly located in the distal esophagus. For the most accurate diagnostic results, biopsies should be taken from the ulcer margins, where signs of viral activity are most evident. Histological examination often reveals multinucleated giant cells with ground-glass nuclei and eosinophilic inclusions, which are characteristic of this condition. Acute HSV-1 infections can be identified through serological analysis, showing positive IgM and negative IgG. This pattern may also be observed in HSV-2 infections, though less frequently[18]. A treatment course with oral acyclovir 200 mg five times a day or 400 mg three times a day for 7-10 days can lead to faster improvement. Famciclovir (500 mg two times daily) or Valacyclovir (1 g two times daily) can also be considered alternative oral therapy, although there is limited experience with these drugs in HSV esophagitis[18,19].

IEUs

IEUs occur in around 10% of HIV patients, either during acute retroviral syndrome or in advanced HIV (CD4 < 50/uL) due to severe immunodeficiency. They are typically seen in the middle esophagus and present as a single ulcer that is enormous (5-10 cm) in size, oval, and has a profound depth. The exact pathogenesis is unknown, and the diagnosis is based on exclusion, necessitating repeated negative biopsies that are negative for infectious processes. Odynophagia is the main symptom of IEUs. A review of the current literature shows that there are no prospective, placebo-controlled, randomized, double-blind trials on the specific therapy of IEU, but according to case reports, oral corticosteroid treatment appears to be a reliable and secure therapy for HIV-related IEU. The response rate to steroids can be 92%-96%. Alternatively, thalidomide 200 mg orally daily for a 28-day course has been reported to be effective[20].

Pill esophagitis

Pill-induced esophagitis in HIV patients is an under-recognized condition that requires greater awareness among healthcare providers. Often, the high burden of antiretroviral treatment, combined with improper techniques like taking pills before sleeping or lying down and insufficient water intake, leads to damage to the esophageal mucosal lining. Zidovudine, Didanosine, and Stavudine, commonly used in highly ART (HAART), can lead to esophagitis. Common symptoms include dysphagia, odynophagia, chest discomfort, heartburn, and retrosternal irritation. To reduce the risk of such injuries, it is crucial for patients to take medications with plenty of water and to remain upright–sitting or standing–for at least 30 minutes afterward[21].

Esophageal malignancies and other conditions

Esophageal malignancies, such as KS and lymphoma, provide a major challenge to HIV patients because of their aggressive nature and complicated therapy. KS is the most common GI malignancy in AIDS, affecting 40% of patients, and is often asymptomatic[22]. The best imaging modality for diagnosing GI KS is port venous-enhanced computed tomography (CT). CT scans of individuals with disseminated illness show enhanced lymph nodes in around 80% of cases[23]. KS masses usually have a polypoid appearance and are usually less than 3 cm, while bigger masses may sometimes arise. Radiological evaluations, endoscopy, and biopsy are necessary for the diagnosis. Radiation treatment, chemotherapy, surgery, and antiretroviral therapy are examples of management techniques[24].

In addition to infections and ulcers, HIV patients may also have problems with neuropathic pain and esophageal motility. HIV neuropathy can lead to GI discomfort and is usually managed symptomatically with metoclopramide and other prokinetic medicines. HIV's neurotrophic properties may also cause irregularities in esophageal motility, which can lead to autonomic dysfunction in the GI, and neurologic plexus[25].

GASTRIC DISORDERS

While the stomach is usually unaffected by opportunistic infections, HIV patients often experience abdominal discomfort, nausea, or vomiting. Common gastric conditions in these patients, like the general population, include gastritis, GERD, and peptic ulcer[26]. The incidence of Helicobacter pylori, a frequent cause of PUD in non-HIV positive people, seems to be lower in HIV patients; instead, CMV is the leading cause of peptic ulcer disease in these patients. Chronic gastritis is a common finding, however, the incidence of acute gastritis in the gastric antrum is lower in severely immunodeficient patients compared to their HIV-negative counterparts[27]. These patients also have concurrent elevated pH, which influences drug absorption and can predispose patients to gastric colonization by pathogens like Candida albicans[28]. Proton-pump inhibitors and histamine-2 blockers which are commonly used for symptomatic management might also interfere with HAART[8]. Thus, caution must be given when prescribing these Dyspepsia is a prevalent complaint among HIV-infected individuals on HAART, often accompanied by mucosal alterations such as erythema, erosion, and ulcers upon endoscopic evaluation[29]. Despite these observations, conflicting findings exist regarding the extent of gastric acid impairment in non-AIDS HIV-1-infected individuals. While some studies have reported no significant alterations, others have documented notable changes in reduced gastric acid output[30].

Studies have also shown that patients with HIV have motor activity disturbances secondary to damage to the peripheral and central autonomic nervous system. As a result, various patterns of gastric emptying, with delayed emptying of solids and accelerated emptying of liquids, have been observed in HIV-positive individuals compared to healthy controls[31]. The other common gastric pathologies include gastric lymphoma, KS, and a few opportunistic infections (including CMV, TB, toxoplasmosis, and cryptococcosis)[26]. GI toxoplasmosis is relatively rare, affecting only 6%-20% of patients with disseminated disease. The symptoms can range from diarrhea and abdominal pain to nausea, vomiting, anorexia, and ascites. Typical endoscopic findings include thickened gastric folds, ulcerative lesions, and general inflammation[32]. Gastric cryptococcus is primarily asymptomatic but, when symptoms do occur, it includes odynophagia, diarrhea, nausea, vomiting, and melena. Gastric cryptococcus is most identified during post-mortem autopsies[33].

DIARRHEA IN HIV PATIENTS

Acute and chronic diarrhea are major complications of HIV infection and AIDS, which leads to significant morbidity and increased healthcare costs[34,35]. Diarrhea has been noted in up to 50% of the AIDS patients in North America, with numbers approaching 100% in the developing world. Previous studies have shown that patients are more likely to experience diarrhea compared to patients without HIV (28% vs 7%, P < 0.001)[34]. The etiology of diarrhea in HIV-infected patients is multi-factorial. Infections, HIV-enteropathy, HAART-associated diarrhea, autonomic neuropathy, and chronic pancreatitis are among the common causes (Table 2). With the introduction of ART, a decline in infectious diarrhea along with a rise in non-infectious diarrhea has been noted. In this section, we will focus on infectious etiologies and HAART-associated diarrhea[35]. The impact on quality of life is illustrated in a national survey in which 40% of HIV patients reported that diarrhea negatively affected their social lives, causing them to alter their daily schedules and develop feelings of shame. Therefore, thorough workup is essential when an HIV patient presents with diarrhea (Figure 2).

Figure 2 Clinical strategy for management of human immunodeficiency virus positive patients presenting with complaints of diarrhea. ART: Antiretroviral therapy; HAART: Highly active ART; HIV: Human immunodeficiency virus.

Table 2 Common opportunistic pathogens in human immunodeficiency virus-associated diarrhea-location, presentation, diagnosis and treatment.

Pathogen	Location	Clinical features	Diagnosis	Chemoprophylaxis	Treatment
Cytomegalovirus	Gastric, small bowel (ileum), and large bowel (colon)	Bloody diarrhea, fever, weight loss, fever, anorexia, abdominal pain	DNA PCR from stool sample	None recommended	IV ganciclovir for 21 to 42 days (can with to oral valganciclovir once the patient can tolerate)
Herpes simplex	Anorectal	Tenesmus, rectal pain, hematochezia, proctitis	DNA PCR for cutaneous lesion	None recommended	Acyclovir/Valacyclovir PO for 5 to 10 days
Cryptosporidium	Gastric, small bowel (ileum), and large bowel	Acute/Subacute onset watery diarrhea, nausea/vomiting, lower abdominal cramping	Microscopic identification of the oocysts in stool with acid-fast staining or direct immunofluorescence	None recommended	Nitazoxanide (500/1000 mg POD BID for 14 days) or paromomycin (500 mg PO QID for 14 to 21 days)
Microsporidia	Small and large bowel	Diarrhea with cramps and abdominal pain, wasting, malnutrition	Microscopic identification of the spores in stool with trichrome staining	None recommended	For Enterocytozoon bieneusi–nitazoxanide 500 mg BID for 14 days. For intestinal infection caused by microsporidia other than E. bieneusi–albendazole 400 mg BID for 14 days
Isospora belli	Gastric	Watery diarrhea, with abdominal pain, cramping, nausea/vomiting, low-grade fever, dehydration	Microscopic identification of the oocysts in stool with acid-fast staining or UV fluorescence microscopy	None recommended. Indirect evidence of a protective effect of TMP-SMX	TMP-SMX (160/800mg QID for 10 days)
Cyclospora	Small bowel	Watery diarrhea, weight loss, abdominal cramping, low-grade fever	Microscopic identification of the oocysts in stool with acid-fast staining	None recommended	TMP-SMX (160/800 mg PO BID for 14 days) or nitazoxanide (500 mg PO BID for 7 days)
Entamoeba histolytica	Colon	Diarrhea with blood and mucus, cramping lower abdomen pain, bloating, fever, chills	DNA PCR from stool sample, stool antigen test, microscopic identification of the cysts/trophozoites in stool	None recommended	Metronidazole 500-750 mg PO TID for 5-10 days or tinidazole 2 g PO once daily for 3 days, followed by a luminal agent
Histoplasmosis	Terminal ileum and colon	Intermittent bloody diarrhea, abdominal pain, fever, weight loss	EIA for urine or serum antigen. Histopathological examination using GMS stain	Itraconazole for patients with CD4 counts < 150/mm3	IV liposomal amphotericin B (3 mg/kg daily) for ≥ 2 weeks or clinical improvement with stepdown to oral itraconazole
Mycobacterium tuberculosis	Terminal ileum and cecum	Abdominal pain, diarrhea, fever, weight loss, night sweats, fatigue	Acid-fast staining	None recommended	Initial phase (2 months): Isoniazid 300 mg daily, rifampin 600 mg daily, pyrazinamide 25 mg/kg daily, and ethambutol 15 mg/kg daily. Continuation phase (4-7 months): Isoniazid 300 mg daily and rifampin 600 mg daily
Mycobacterium avium complex	Small bowel and large bowel	Fever, abdominal pain, weight loss, night sweats, fatigue	Acid-fast staining	Azithromycin for patients with CD4 count < 50/mm3	Clarithromycin (7.5 to 15 mg/kg PO BID for at least 12 months)

PCR: Polymerase chain reaction; PO: Per Os (by mouth/orally); BID: Bis in die (twice daily); QID: Quater in die (four times daily); TMP-SMX: Trimethoprim-Sulfamethoxazole; GMS: Grocott's methenamine Silver; EIA: Enzyme immunoassay.

Infectious diarrhea

Previous studies have noted that approximately 44% to 82% of cases of chronic diarrhea in HIV patients have an identifiable infectious etiology[36-39]. However, in resource risk settings, the infectious etiology has been noted in as low as 12% of patients with diarrhea[40]. However, infections continue to be highly endemic in resource-limited settings, with chronic diarrheal disease being used as a predictor for HIV-seropositivity in certain populations. Table 2 highlights the various infectious causes of diarrhea in HIV patients along with the recommended management options.

HAART-associated diarrhea

Since the introduction of HAART therapy, there has been a significant reduction in the incidence of infectious diarrhea. However, at the same time, there has been a steady increase in the incidence of medication-induced, such that it is the leading diagnostic consideration when diarrhea is the sole complaint, particularly when there is a temporal association[40]. Up to 12.5% of patients taking post-exposure prophylaxis experience diarrhea[41]. GI complications continue to be one of the major reasons for discontinuing retroviral treatment and associated reduced quality of life. Up to 19% of the patients treated with HAART reported moderate to potentially life-threatening diarrhea, which can be related to the study drug[42].

Diarrhea has been noted with all main classes of ARVs: Nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitor, PIs, and integrase inhibitors[43,44]. Among these medications, ritonavir, which is used in combination with other PIs, is most commonly associated with diarrhea. Lopinavir/ritonavir and fosamprenavir/ritonavir have been noted to have the highest incidence (10%-15%) compared to the other combinations[45,46]. Poor adherence and switching regimes also increase the risk of development of resistance to virological treatment. Various mechanisms have been proposed for the occurrence of diarrhea. Nefinavir is noted to enhance calcium signaling in the secretory epithelial cells leading to the loss of chloride ions across the epithelial membrane, leading to secretory diarrhea[47]. Ritonavir on the other hand has demonstrated cell apoptosis and disruption of intestinal epithelial barrier integrity leading to diarrhea[48].

Management options included probiotics, antimotility, and antisecretory agents. Crofelemer is an antisecretory drug that inhibits chloride channels in the gut, which are responsible for large-volume water loss. In a randomized controlled trial of 376 HIV patients on HAART, Crofelemer was noted to significantly reduce diarrheal symptoms compared with placebo (clinical response defined as ≤ 2 watery stools/week during ≥ 2 of 4 weeks; 17.6 vs 8.0%; P ¼ 0.01)[49]. Pharmacokinetic studies have shown that systemic absorption of Crofelemer is minimal, with over 95% of subjects having serum levels below the quantifiable threshold[50]. Importantly, Crofelemer does not exhibit significant interactions with antiretroviral therapies[51].

HIV enteropathy

HIV enteropathy is an idiopathic form of diarrhea in HIV-infected individuals, characterized by the absence of identifiable pathogens and diagnosed by exclusion. It is associated with increased inflammation and immune activation and decreased mucosal repair and regeneration. It is also known as the ‘Slim disease’, in recognition of the severity of weight loss caused[52]. Chronic diarrhea, malabsorption, increased intestinal permeability and malnutrition are common clinical manifestations. The primary goal of managing HIV enteropathy is to prevent further depletion of CD4+ T lymphocytes, incorporating the initiation of HAART alongside supportive care. Previous studies highlighting the improvement in clinical signs and symptoms support the initiation of HAART[53]. Additionally, adjunctive therapies, including antimotility agents, antisecretory drugs (Crofelemer as discussed in the previous section), adsorbents, and opioids, are utilized to manage symptoms[54].

COLITIS

Bloody diarrhea and tenesmus are frequent symptoms of colitis in HIV patients. These conditions are often brought on by bacterial infections such as Shigella, E. coli, Campylobacter jejuni, and Clostridium difficile. HIV individuals are much more likely to get salmonellosis, for which ciprofloxacin is used as a therapy[55]. While Campylobacter jejuni usually causes watery diarrhea, Shigella presents similarly. Ciprofloxacin is a medication that treats a variety of enteric diseases, including E. coli infections[56]. When Clostridium difficile-related colitis is detected by toxin assay and treated with metronidazole or tinidazole, it may happen even in the absence of recent antibiotic medication. Amphotericin B and itraconazole are used to treat fungus-related diarrhea, which is uncommon and often occurs with systemic diseases such as GI histoplasmosis. HIV patients may also have GI problems from non-infectious reasons, such as drug-induced diarrhea from antiretroviral drugs, inflammatory bowel disorders, lymphoma, and Kaposi's sarcoma[57]. Each of these conditions calls for a different diagnosis and treatment strategy.

SMALL BOWEL LYMPHOMA

Although primary small bowel lymphoma is an uncommon condition, its prevalence is rising, especially in those living with HIV. As you go proximally in the small intestine, the incidence of this lymphoma decreases, mostly affecting the terminal ileum. AIDS is often diagnosed in people with non-Hodgkin's lymphoma or small bowel lymphoma[58].

Spoken thickening of the intestinal wall (between 1 and 7 cm), fungating masses, tumor infiltration of the myenteric nerve plexus resulting in aneurysmal intestine dilatation, and, less often, solid mass lesions are among the radiological characteristics of small bowel lymphoma. In one case, for example, a 50-year-old man with a CD4 count of 190 cells/μL showed signs of lymphadenopathy, upstream small intestinal dilatation, circumferential thickening of the terminal ileum and caecum, and lymphomatous infiltration of the ileocaecal valve. Further pathological examination confirmed the non-Hodgkin's lymphoma diagnosis[59]. This manifestation emphasizes how crucial it is to keep an eye on and manage GI issues in HIV patients, as these illnesses may have detrimental effects and call for specific diagnosis and treatment plans.

ANORECTAL DISORDERS

The frequency of anorectal disease is unchanged by ART, which makes it a significant issue for HIV patients, especially gay men. Numerous anorectal diseases affect this population, such as proctitis, fissures, ulcerations, perirectal abscesses, and anal fistulas. Add to this the possibility of anal neoplasms associated with the human papillomavirus (HPV) and other variables, and anorectal carcinoma ranks fourth among malignancies in HIV patients; it is more prevalent among homosexual men who are HIV positive[59]. Anorectal cytology may identify anal squamous cell carcinoma, which is similar to cervical cancer screening in that it is often linked to squamous intraepithelial neoplasia associated with HPV. While anoscopy combined with biopsy is still the preferred method of diagnosis, anorectal cytology may be a helpful screening tool[6].

Other common anorectal symptoms in the HIV population include proctitis, which is frequently brought on by infectious agents such as gonorrhea, herpes simplex, chlamydia, and syphilis and requires the use of an appropriate antibiotic or antiviral therapy, and anal condyloma associated with HPV infection, which can be treated with a variety of surgical options[60]. Furthermore, overlapping clinical presentations may result from colitis caused by various sources, such as lymphogranuloma venereum. Essential diagnostic instruments for evaluating anorectal disorders, identifying opportunistic infections, and directing treatment choices include associative sigmoidoscopy and anoscopy combined with mucosal biopsies.

ANAL SQUAMOUS CELL CARCINOMA

HPV infection is a common cause of anal squamous cell carcinoma, which is more common in HIV-positive persons because of the higher risk of co-infections, especially via anoreceptive sexual relations[60]. While HIV is not a direct cause, it is a marker for increased vulnerability to STDs such as HPV, with those who are positive for the virus seven times more likely to have persistent HPV[5]. Magnetic resonance imaging (MRI) is the recommended imaging modality for evaluating anal malignancies. It offers comprehensive details on the tumor's location, size, and local invasion. When using T1-weighted imaging, T2-weighted imaging, or short tau inversion recovery sequences, malignant tissue located inside the anal canal usually exhibits low signal intensity, intermediate signal intensity, or lower signal intensity than ischioanal fat[61].

Anal squamous cell carcinoma appears on CT images as a solid, enhancing mass that becomes larger and more amorphous. In one example, T2-weighted imaging revealed a massive soft tissue mass with significant soft tissue invasion in a 42-year-old male HIV-positive patient with a CD4 level of 16 cells/μL[59]. The mass's signal strength was moderate, meaning it was less than that of the adipose tissue around it. This manifestation highlights how crucial it is for HIV-positive people to get routine monitoring and early identification to treat potentially dangerous GI side effects including anal squamous cell carcinoma.

GI TB

Global health concerns about TB persist, particularly concerning those living with HIV. Up to 70% of HIV patients are predicted to have TB at some time in their life. When the CD4 count falls, TB risk rises dramatically, reaching a crucial threshold of around 200 cells/μL. In those who are HIV-positive, lung TB often leads to intestinal TB[55].

Although TB in the abdomen may infect any section of the GI system, this is the area most often affected because of the large concentration of lymphoid tissue in the terminal ileum. Abdominal TB manifests on CT or MRI scans as circumferential thickening of the afflicted intestine segment, sometimes with adjacent lymphadenopathy[56]. These imaging characteristics, however, are often non-specific and may be confused with illnesses like cancer or inflammatory bowel disease.

Asymmetric thickening of the medial wall of the caecum and terminal ileum, together with significant lymphadenopathy with central regions of diminished attenuation, are indicative signs. Research involving two patients with abdominal TB revealed that at the time of presentation, their CD4 Levels were both less than 100 cells/μL[59]. These instances underscore the need to identify GI TB as a plausible complication in patients living with HIV/AIDS and the necessity of exercising caution in both diagnosis and treatment.

PANCREATITIS

The interplay between HIV and the pancreas encompasses a complex array of direct viral effects, indirect consequences, and complications arising from ART. Notably, HIV-infected patients may present with various pancreatic abnormalities, including acute pancreatitis, which is influenced by factors such as prolonged HIV seropositivity, exposure to PIs, immunodeficiency, AIDS, chronic liver and/or biliary disease, and hypertriglyceridemia[62]. This underscores the ongoing concern regarding the management and assessment of pancreatitis risk in such settings. Compared to the general population, HIV-infected individuals exhibit a heightened incidence of acute pancreatitis, with risk factors including severe immunosuppression, female gender, and specific medication usage such as stavudine and aerosolized pentamidine[63]. PIs used in ART have been implicated in inducing insulin resistance and diminishing insulin secretion by pancreatic beta cells via inhibition of glucose translocation through glucose transporter 4[64].

Moreover, an inverse relationship exists between serum pancreatic enzyme levels and CD4 Lymphocyte counts, suggesting a link between immunosuppression and pancreatic inflammation[57]. Non-infectious complications, notably non-Hodgkin's lymphoma, can also involve the pancreas in HIV-infected patients[65]. Furthermore, exocrine pancreatic insufficiency has been identified in HIV-infected individuals, contributing to malabsorption and growth alterations, particularly in pediatric populations[64,66]. The prevalence of exocrine pancreatic insufficiency among HIV-infected patients on suppressive ART remains significant, with some responding to pancreatic enzyme replacement therapy[67]. In summary, HIV infection impacts the pancreas through diverse mechanisms, including direct viral effects, ART-related toxicity, and associated opportunistic infections or malignancies. Clinicians should maintain vigilance for signs of pancreatic involvement in HIV-infected patients, as it can significantly contribute to morbidity and complicate the management of HIV disease.

CONCLUSION

In conclusion, there is a complex connection between HIV infection and a variety of GI symptoms. It highlights how important it is to comprehend and treat these GI disorders, which can range from diarrhea, enteritis, colitis, and esophageal problems to anorectal diseases, anal squamous cell carcinoma, GI tuberculosis, liver disorders, and pancreatitis. Early diagnosis of HIV and identifying the underlying causes of associated GI conditions are essential. The research also highlights the evolving patterns of GI disease since the introduction of HAART, with a decline in infectious GI complications in developing countries and a rise in those related to medication side effects and direct viral injury. Recognizing how factors like medication use and local dietary habits influence these changing patterns is key to effectively managing these patients. Addressing these GI issues is crucial for improving the quality of life in HIV-positive individuals and reducing the burden of these complications as HIV treatments continue to advance.