Gastrointestinal disease in patients with HIV infection

Ian Lockart : Department of Gastroenterology and Hepatology, St Vincent's Hospital, Sydney NSW
Deborah J. Marriott : Immunology/HIV/Infectious Diseases Clinical Services Unit, St Vincent’s Hospital, Sydney NSW
Mark Danta : Department of Gastroenterology and Hepatology, St Vincent's Hospital, Sydney NSW 

General approach to the assessment of gastrointestinal symptoms in HIV patients

Gastrointestinal symptoms and illnesses are extremely common in the general population and also in patients with human immunodeficiency virus (HIV) infection. When assessing this, we need to take into account:

  1. Detailed history of presenting symptom including: Onset, severity, site/location, frequency and progression, triggering and relieving factors, associated features such as fevers and weight loss. 
  2. Degree of immunodeficiency: CD4 T- lymphocyte (CD4) cell count - opportunistic infections, such as cytomegalovirus (CMV) colitis, occur in advanced immunodeficiency. Duration of CD4 cell depletion. Additional immunosuppressive factors (e.g. corticosteroids, immunosuppressant therapy).
  3. Use of primary and secondary prophylactic therapy for gastrointestinal tract pathogens: Azithromycin for Mycobacterium avium complex (MAC), Valganciclovir for CMV (including dose and adherence).
  4. Risk behaviour and activities: Injecting drug use – increased risk of hepatitis B virus (HBV), hepatitis C virus (HCV) and bacterial sepsis. Sexual history, particularly for men who have sex with men – risk of enteric pathogens and sexually transmitted proctitis.  Recent travel – risk of parasitic infections, hepatitis A virus infection and typhoid. Recent infectious contacts.
  5. Past medical history and family history - previous endoscopy/colonoscopy, family history of inflammatory bowel disease.
  6. Medications: Prescribed (including antibiotics) and over-the-counter.
  7. Previous abdominal surgeries - cholecystectomy, appendicectomy or other surgery.
  8. Gynaecological history in women.

Common symptoms and signs reported in patients with HIV and the more common causes are presented in Table 1 along with a number of associated features and differential diagnoses that are particularly important to consider in patients with HIV.

 

Table 1. Common gastrointestinal symptoms, signs and their causes to consider in patients with HIV
Symptoms

Concerning associated features

Common causes

HIV-associated causes

Investigations to consider

Dysphagia/ odynophagia

Weight loss

Rapidly progressive; solids initially and liquids later

Iron deficiency anaemia, gastrointestinal bleeding

Peptic stricture

Eosinophilic oesophagitis

Oesophageal webs and rings

Achalasia and other oesophageal motility disorders

Oesophageal cancer

Food bolus

Oesophageal candidiasis

Viral oesophagitis –  CMV, HSV

Upper gastrointestinal endoscopy

Barium swallow

Diarrhoea

Blood or mucus in the stool

Recent travel

Recent antibiotics

Large volume, watery diarrhoea

Weight loss

Prolonged symptoms

Significant abdominal pain

Fevers/rigors

Viral gastroenteritis

Bacterial enterocolitis, including salmonellosis

Clostridium difficile colitis

Parasite infections

Coeliac disease

Inflammatory bowel disease

Irritable bowel syndrome

CMV colitis

MAC enterocolitis

Cryptosporidiosis Microsporidiosis

HIV protease inhibitors

Lymphoma

Kaposi sarcoma

HIV enteropathy

FBC, U+E, LFT, CRP

Stool culture and microscopy

Clostridium difficle toxin

Blood cultures - for MAC

Colonoscopy and colonic biopsy

CT scan of the abdomen-pelvis

Rectal bleeding

Weight loss

Recent hange in bowel habit

Tenesmus

Family history of colorectal cancer

Haemorrhoids

Anal fisures

Proctitis

Colorectal tumours

Anal tumours

Digital rectal exam

Anoscopy

Sigmoidoscopy

Colonoscopy

Abdominal pain

Acute vs. chronic

Weight loss

Persistent diarrhoea

Rectal bleeding

Ascites

 

Gastroenteritis

Inflammatory bowel disease

Irritable bowel syndrome

Appendicitis

Diverticulitis

Cholecystitis

Pancreatitis

Bowel obstruction

Opportunistic infections - CMV, MAC

Neoplasms - Lymphoma, Kaposi Sarcona

CT scan of abdomen

Upper abdominal ultrasound

Endoscopy and colonoscopy

Jaundice

Fevers

Pain v's painless

Weight loss

Substance abuse

Ascites

Encephalopathy

Alcoholic hepatiits

Viral hepatitis

Choledocholithiasis

Pancreatic cancer

Haemolysis

Medications

Gilbert's syndrome

Atazanavir

Lymphoma

AIDs cholangiopathy

LFTs, INR, LDH

Conjugated and unconjugated bilirubin

Ultrasound of biliary tree

CT scan of abdomen 

MRCP

ERCP

CMV: cytomegalovirus; CRP: C-reactive protein; CT: computerised tomographic; ERCP: endoscopic retrograde cholangiopancreatography; FBC: full blood count;  HSV: herpes simplex virus; INR: international normalised ratio for prothrombin time; LFT: liver function test; LDH: lactate dehydrogenase; MAC: Mycobacterium avium complex; MRCP: magnetic retrograde cholangiopancreatography; U+E: urea and electrolytes

Specific gastrointestinal and oral infections associated with HIV infection

The following section will discuss the diagnosis and management of a number of common bacterial, viral and parasitic gastrointestinal infections and also non-infectious diarrhoea. A number of important HIV-associated conditions are covered elsewhere in the monograph - oesophageal candidiasis, CMV infections, Kaposi sarcoma and HBV and HCV infection. Readers are referred to other text for management of common illnesses such as gastroesophageal reflux disease and the Australian antibiotic guidelines [1][2] and Sanford Guides[3] for specific treatment advice.

Dysphagia/ Odynophagia

When assessing patients with dysphagia (difficulty swallowing with a sensation of food sticking) it is important to determine if their symptoms are due to an oropharyngeal or an oesophageal cause.  Patients with oropharyngeal dysphagia often have difficulty initiating a swallow, reporting a sensation that food gets stuck immediately on swallowing (usually localising/pointing to their necl) and may experiencing coughing, choking or nasal regurgitation during swallowing.  Patients with oesophageal dysphagia usually report a sensation of food getting stuck soon after swallowing (they may localise/point to their neck or behind their sternum).  Oesophageal dysphagia may be due to structural or motility disorders.  A detailed history can give clues to the likely cause.  The types of food that produce symptoms (solids, liquids or both), the changes over time (types of food at onset, intermittent or progressive natue) and associate symptoms (pain, heartburn, regurgitation, weight loss) should be ascertained.  Previous interventions (surgery, radiotherapy), other disease (allergies, asthma, eczema) and other medications (tetracyclines, bisphosphonates) may be relevant.

Oesophageal candidiasis is the most common cause of dysphagia in patients with HIV infection.  Patients may also report odynophagia and retrosternal discomfort.  Most patients will also have oropharyngeal candidiasis (oral thrush), however, its absence does not rule it out [4].  An upper gastrointestinal endoscopy is generally not required for diagnosis for patients with HIV and oral thrush with oesophageal symptoms.  Treatment consists of a loading dose of 200mg, then 100-200mg of oral fluconazole for 14-21 days.[5][6].  Intravenous fluconazole can be used for patients who are unable to tolerate oral therapy.  For patients with a poor clinical response to oral fluconazole, an upper gastrointestinal endoscopy is necessary to exclude other diagnosis (such ans CMV and HSV) and to obtaine specimens for fungal speciation and antifungal susceptibility testing.  The management of oesophageal candidiasis, including treating resistnat infections, relapses and maintenance thearpy, is discussed in detal in the Key Opportunistic Infections section on oesophageal candidiasis.

HSV and CMV disease should be considered in patients presenting with odynophagia (pain on swallowing) as their prominent complaint. HSV oesophagitis usually has a severe and abrupt onset of intense pain (reviewed in Lavery et al.[7]). CMV oesophagitis is more subacute and associated with weight loss. The absence of oral lesions (herpes labialis) does not exclude the diagnosis of HSV oesophagitis. An endoscopy and biopsy is required to confidently distinguish these two conditions. HSV oesophagitis responds to aciclovir 5 mg/kg intravenously every 8 hours followed by famciclovir 500mg twice a day or valaciclovir 1g twice a day when oral therapy is possible to complete a 10-day course.[8] Maintenance therapy is usually reserved for frequent recurrences. The management of gastroinetstinal infection with CMV is discussed in the Key Opportunistic Infections section on cytomegalovirus.

Diarrhoea

Diarrhoea is common amongst patients with HIV infection.  The differential diagnosis is strongly influenced by the durations of symptoms (acute versus chronic) and the degree of immunodeficiency.  Patients with advanced immunodefiiciency are at risk of opportunistic infections such as cytomegalovirus (CMV) infection and disseminated mycobacterium avium complex (MAC); these diseases are rarely seen in Australia.  A detailed clinical history and physical examination is essential.  Investigations should include stool culture and microscopy, including three samples to assess for ova, cysts and parasites.  Additional investigations that may be required include blood cultures, endoscopy with biopsies and abdominal imaging with CT.  Causes of acute and chronic diarrhoea that also occur in patients without HIV infection should also be considered.

Enteric pathogens causing diarrhoea

Acute, infective diarrhoea is common in patients with HIV infection. Transmission may be foodborne, waterborne, or person-to-person via faecal-oral or sexual routes, and institutional. The patterns of infecting enteric pathogens vary based on patient and geographical epidemiology. In resource-rich Australia, bacterial pathogens such as salmonella, shigella and campylobacter are common. Common viral infections such as norovirus and adenovirus are mostly self-limiting.  A history of unprotected, receptive anal intercourse may suggest sexually transmission of organisms such as Neisseria gonorrhoea or Chlamydia and proctitis.  Clostridium difficile is most common after antibiotic usage. Parasitic infections are rare except in returning travellers.  (see Table 2).

Table 2 Common causes of diarrhoea in patients with HIV infection in Australia – clinical presentation, diagnosis and management[9][10]
  Clinical presentation Diagnosis Management Comments
Salmonella spp. Abrupt onset of watery diarrhoea, nausea, abdominal pain and fevers occurring 6-48 hours post-contact

Stool MCS        Blood culture

IV ceftriaxone initially if bacteraemic, then oral azithromycin or ciprofloxacin for 5 to 7 days Look for bacteraemia. Patients may be bacteraemic without diarrhoea
Shigella spp. Fever, non-bloody watery dysentery (usually 1-7 days post-contact) Tenesmus

Stool MCS    Blood culture

Oral ciprofloxacin for 5 days Strict rules for food handlers
Campylobacter spp. Voluminous watery diarrhoea early, then proctocolitis with blood, mucous and tenesmus (usually 2-6 days post-contact) Stool MCS    Blood culture Oral azithromycin or ciprofloxacin for 3 days Look for bacteraemia. Patients may be bacteraemic without diarrhoea
Clostridium difficile Diarrhoea, fever, abdominal pain Antibiotic exposure Clostridium difficile toxin Metronidazole 400 mg three times a day or alternatively oral vancomycin 125 mg four times a day for 10-14 days Contact isolation in health services
Norovirus Acute watery diarrhoea Faecal Multiplex PCR  Is usually self-limiting. No antiviral therapy required Contact isolation in health services
Giardia Non-bloody, chronic diarrhoea occurring 1-3 weeks post-exposure associated with nausea, vomiting, abdominal pain, belching, bloating and flatus. Fevers are rare Red cells are rare. Cysts and trophozoites Tinidazole 2 g single dose -

MCS: microscopy culture sensitivities; spp: species

Chronic infective diarrhoea caused by unusual parasites such as Cryptosporidium parvum, microsporidia, Cyclospora cayetanensis and Cystoisospora belli are now rarely seen in resource-rich settings. These are associated with advanced immunodeficiency and patients present with profuse prolonged diarrhoea associated with anorexia, fatigue and weight loss and occasional fevers. Giardia is still occasionally encountered (Table 2). A travel history is helpful. Careful stool examination for ova, cysts and parasites may require special stains such as modified acid-fast and auramine-rhodamine fluorescent stains. Althrough rare in Australia, amongst patients with advanced immunodeficiency, Mycobacterium avium complex (MAC) should be considered and appropriate blood cultures obtained.   Endoscopy with biopsies should be considered, particularly when considering gastrointestinal infection with cytomegalovirus (CMV).

Non-infectious diarrhoea

While antiretroviral therapy (ART) has clearly reduced the incidence of diarrhoea due to opportunistic infections, up to a quarter of patients receiving ART are estimated to experience four or more loose motions a day. Non-infectious diarrhoea may be associated with ART, or HIV-infection itself (HIV enteropathy). Protease inhibitors have the highest rates of diarrhoea (13.3%) compared to nucleoside reverse transcriptase inhibitors (NRTIs) (10%, excluding stavudine and didanosine – no longer commonly used) and 2% in non-nucleoside reverse transcriptase inhibitors (NNRTIs).[11] ART-associated diarrhoea has been postulated to be due to damage to the intestinal epithelial barrier and altered secretion of calcium-dependent chloride ions. HIV enteropathy has been proposed to be due to viral infection of enterocytes leasing to a loss of epithelial barrier and permeability, immune activation and loss of autonomic denervation.[12]

Dietary, non-pharmacological and pharmacological approaches should be attempted before switching ART from a successful regimen. Clinical trials in this area are limited. Proposed modifications include: reduction in caffeine, fat and lactose intake; and increase in fibre consumption. Psyllium husk and oat bran, as bulking agents, and probiotics or bovine serum-derived immunoglobulin, to modulate and normalise enteric flora, have also been used.[13] Pharmacological treatment includes adsorbents (e.g. bismuth), antimotility agents (e.g. loperamide) and antisecretory agents such as octreotide.[14][15] Crofelemer, a novel dual inhibitor of cAMP-stimulated CFTR (cystic fibrosis transmembrane conductance regulator) chloride channel and CaCC (calcium-activated chloride channel), has shown promising results.[16]

1.
Antibiotic Expert Groups. Therapeutic guidelines: antibiotic. Version 15. Melbourne: Therapeutic Guidelines Limited; 2014 
2.
Gastrointestinal Expert Group. Therapeutic guidelines: gastrointestinal. Version 6. Melbourne: Therapeutic Guidelines Limited; 2016 
3.
Saag MS, Pavia AT, Chambers HF, Eliopoulos GM, Gilbert DN. The Sanford Guide to HIV/AIDS Therapy. 25 edition. Sperryville: Antimicrobial Therapy Inc; 2017 
4.
Wilcox CM, Straub RF, CLark WS. Prospective evaluation of oropharyngeal findings in human immunodeficiency virus-infected patients with esophageal ulceration. Am J Gastroenterology. 1995;90(11):1938. 
5.
Gastrointestinal Expert Group. Therapeutic guidelines: gastrointestinal. Version 6. Melbourne: Therapeutic Guidelines Limited; 2016 
6.
Saag MS, Pavia AT, Chambers HF, Eliopoulos GM, Gilbert DN. The Sanford Guide to HIV/AIDS Therapy. 25 edition. Sperryville: Antimicrobial Therapy Inc; 2017 
7.
Lavery EA, Coyle WJ. Herpes simplex virus and the alimentary tract. Curr Gastroenterol Rep 2008;10:417-23 
8.
Gastrointestinal Expert Group. Therapeutic guidelines: gastrointestinal. Version 6. Melbourne: Therapeutic Guidelines Limited; 2016 
9.
Antibiotic Expert Groups. Therapeutic guidelines: antibiotic. Version 15. Melbourne: Therapeutic Guidelines Limited; 2014 
10.
Saag MS, Pavia AT, Chambers HF, Eliopoulos GM, Gilbert DN. The Sanford Guide to HIV/AIDS and viral hepatitis therapy. 25 edition. Sperryville: Antimicrobial Therapy Inc; 2017 
11.
Clay PG, Crutchley RD. Noninfectious diarrhea in HIV seropositive individuals: a review of prevalence rates, etiology, and management in the era of combination antiretroviral therapy. Infect Dis Ther 2014;3:103–22 
12.
Clay PG, Crutchley RD. Noninfectious diarrhea in HIV seropositive individuals: a review of prevalence rates, etiology, and management in the era of combination antiretroviral therapy. Infect Dis Ther 2014;3:103–22 
13.
Clay PG, Crutchley RD. Noninfectious diarrhea in HIV seropositive individuals: a review of prevalence rates, etiology, and management in the era of combination antiretroviral therapy. Infect Dis Ther 2014;3:103–22 
14.
Clay PG, Crutchley RD. Noninfectious diarrhea in HIV seropositive individuals: a review of prevalence rates, etiology, and management in the era of combination antiretroviral therapy. Infect Dis Ther 2014;3:103–22 
15.
Dikman AE, Schonfeld E, Srisarajivakul NC, et al. Human immunodeficiency virus-associated diarrhea: still an issue in the era of antiretroviral therapy. Dig Dis Sci 2015;60:2236-45 
16.
Macarthur RD, Hawkins TN, Brown SJ, et al. Efficacy and safety of crofelemer for noninfectious diarrhea in HIV-seropositive individuals (ADVENT trial): a randomized, double-blind, placebo-controlled, two-stage study. HIV Clin Trials 2013;14:261-73