Gastrointestinal disease in patients with HIV infection

Christina C. Chang : Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne VIC
Deborah J. Marriott : Immunology/HIV/Infectious Diseases Clinical Services Unit, St Vincent’s Hospital, Sydney NSW
Jeffrey J. Post : Department of Infectious Diseases and Albion Street Centre, Prince of Wales Hospital and School of Medical Sciences and Prince of Wales Clinical School, University of New South Wales, Sydney NSW
Mark Kelly : Armidale Rural and Referral Hospital, Armidale 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 including: Onset, frequency and progression, site/location Duration and severity Triggering and relieving factors Associated features such as fevers and weight loss
  2. Risk behaviour and activities: Injecting drug use – increased risk of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection and bacterial sepsis Substance abuse – including alcohol Sexual history including men who have sex with men – risk of enteric pathogens, particularly salmonellosis Recent travel – risk of parasitic infections, hepatitis A virus infection and typhoid Recent contacts Dietary habits
  3. 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)
  4. Use of primary and secondary prophylactic therapy for gastrointestinal tract pathogens Azithromycin for Mycobacterium avium complex (MAC) Valganciclovir for CMV (including dose and adherence)
  5. Medications: Prescribed including antibiotics and opiates Over-the-counter including aspirin
  6. Previous serological tests for infection by gastrointestinal tract pathogens
    1. CMV antibodies HBV and HCV antibodies
  7. Previous abdominal 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

Comment
Dysphagia/ odynophagia

Weight loss

Solid vs. liquid

GORD

Oesophageal tumour

Foreign body

Oesophagitis – Candida, CMV, HSV

Barium swallow

Oesophagoscopy with biopsy and/or culture of brushings

-
Nausea/ vomiting

Hematochezia

Weight loss

Right upper quadrant or epigastric abdominal pain

Headache/meningism

Jaundice

Recent travel

Medications GORD

Gastroenteritis

Food-poisoning

Ileus

Colitis

Alcohol

Renal impairment

Sepsis

Acute viral Hepatitis

Pancreatitis

Non-specific

-

FBE, LFT, U+E, Calcium

Targeted: Ultrasound of liver

Ultrasound of renal tract

Gastroscopy

-
Diarrhoea

Bloody diarrhoea

Voluminous watery diarrhoea

Recent travel

Weight loss

Prolonged symptoms

Fevers/rigors

Viral gastroenteritis

Bacterial enterocolitis, including salmonellosis

Clostridium difficile colitis

arasite infections

Lactose intolerance

Inflammatory bowel disease

Irritable bowel syndrome

HIV enteropathy

CMV colitis

MAC enterocolitis

Kaposi sarcoma

Cryptosporidiosis Microsporidiosis

HIV protease inhibitors

Gastric lymphoma

CMV cholecystitis

FBE, CRP, LFT, U+E, Blood cultures, including for MAC

Plasma CMV viral load

Stool cultures and microscopy

Faecal

Clostridium difficile toxin

Colonoscopy and colonic biopsy

-
Constipation Bleeding per rectum (PR) Haemorrhoids Poor diet Opiates

Anal tumours

Colorectal tumours

Anoscopy

Sigmoidoscopy

Colonoscopy

Serum carcinoembryonic antigen

-
Abdominal pain

Acute vs. chronic

Weight loss

Persistent diarrhoea

Bleeding PR Ascites

 

Gastroenteritis

Inflammatory bowel disease

Irritable bowel syndrome

Cholecystitis

Pancreatitis

Bowel obstruction

Appendicitis

Lymphoma

HIV protease inhibitors

CT scan of abdomen

Clarify location of pain to target investigations.

Gynaecological history and examination in women.

Jaundice

Fevers

Weight loss

Substance abuse

Painful vs. painless

Ascites

Liver failure

Cholelithiasis

Acute hepatitis

Excessive alcohol use

Pancreatic cancer

Haemolysis

Medications

Atazanavir Lymphoma

LFT, INR, LDH Ultrasound of liver

CT scan of abdomen Ca 19.9

ERCP/MRCP may be required

CMV: cytomegalovirus; CRP: C-reactive protein; CT: computerised tomographic; ERCP: endoscopic retrograde cholangiopancreatography; FBE: full blood examination; GORD: gastroesophageal reflux disease; 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.

Oral lesions

Gingivitis, periodontitis

Dental hygiene is important in all patients with HIV infection, but particularly challenging in those patients with social, financial and housing difficulties. Smoking, high sugar diets and excessive alcohol intake are risk factors for poor dental hygiene. The common form of gingivitis, linear gingival erythema characterised by a 1-3 mm erythematous band along the gingival margin, periodontitis and oral aphthous ulceration are common in patients with HIV and also the general population. Clinical features include halitosis, spontaneous bleeding and pain. These conditions are usually self-limiting and respond to dental attention and mouth washes. Severe gum disease seen previously in advanced HIV-associated immunodeficiency, such as necrotising ulcerative gingivitis and periodontitis, is now rare.

Oropharyngeal candidiasis

The case definitions of oropharyngeal candidiasis and other oral diseases have been updated by the Oral HIV/AIDS Research Alliance and expertly discussed in Shiboski et al:[4]

  1. Pseudo-membranous candidiasis presents as white or yellow plaques, which may be located in any part of the oral cavity and easily rubbed off. Underlying mucosa may be erythematous and bleed. These are usually painful.
  2. Erythematous candidiasis presents as red areas on the palate, the dorsum of the tongue, and occasionally on the buccal mucosa. This is usually asymptomatic.
  3. Angular chelitis presents as fissuring at the corners of the mouth.

The diagnosis is generally made on clinical appearance, but a plain swab or concentrated mouth rinse for microbiological culture may aid in confirming the diagnosis. In poorly resolving candidiasis, culture results assist in species identification and antifungal resistance profiling. Oral fluconazole 100-200 mg daily for 7-14 days is recommended therapy.[5] A single dose of 750 mg fluconazole has also been shown to be equally effective as 150 mg daily for 14 days.[6] Topical amphotericin B taken four times daily can be administered as a suspension, lozenge or tablet. Oral clotrimazole 10 mg troches/lozenges administered five times daily or nystatin oral drops (Nilstat®) 4-6 mL four times daily can successfully treat mild-to-moderate oropharyngeal candidiasis. Other azoles particularly posaconazole have also been shown to be successful (reviewed in Patton et al.[7]), but are usually only required in fluconazole-refractory disease. Secondary prophylaxis targeted against candida is usually limited to those with recurrent disease and have a CD4 cell count of less than 50 cells/uL.

Dysphagia/ odynophagia

Oesophageal candidiasis, the most common cause of dysphagia (difficulty swallowing with a sensation of food sticking) in patients with HIV infection, is discussed in detail in the section on oesophageal candidiasis. This condition is usually treated with 200-400 mg of oral fluconazole for 14-21 days,[8][9] and endoscopy is performed in the setting of poor clinical response, to rule out CMV and HSV disease.

HSV and CMV disease should be considered in patients presenting with odynophagia (pain on swallowing). HSV oesophagitis usually has a severe and abrupt onset of intense pain (reviewed in Lavery et al.[10]). 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 acyclovir 5 mg/kg intravenously every 8 hours followed by famciclovir or valaciclovir 500 mg twice a day when oral therapy is possible for 14-21 days.[11] Maintenance therapy is usually commenced only after the first relapse. CMV oesophagitis is discussed in the section on dermatological manifestations.

Enteric pathogens causing diarrhoea

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 and campylobacter are common as is Clostridium difficile particularly after antibiotic usage, whereas parasitic infections are rare except in returning travellers. Common viral infections such as norovirus and adenovirus are mostly self-limiting (see Table 2).

MCS: microscopy culture sensitivities; spp: species

Salmonella spp.Abrupt onset of watery diarrhoea, nausea, abdominal pain and fevers occurring 6-48 hours post-contact Stool MC/ Blood culture(IV ceftriaxone if bacteraemic) then oral azithromycin or ciprofloxacin for total of 14 days Look for bacteraemia. Patients may be bacteraemic without diarrhoea

Table 2 Common causes of diarrhoea in patients with HIV infection in Australia – clinical presentation, diagnosis and management[12][13]
  Clinical presentation Diagnosis Management Comments
Shigella spp. Fever, non-bloody watery dysentery (usually 1-7 days post-contact) Tenesmus Stool MCS Blood culture Oral azithromycin or ciprofloxacin for 7-10 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 5-10 days Look for bacteraemia. Patients may be bacteraemic without diarrhoea
Clostridium difficile Diarrhoea, fever, abdominal pain Antibiotic exposure Clostridium difficile toxin Metronidazole 500 mg three times a day or alternatively oral vancomycin 125 mg three times a day for 10-14 days Contact isolation in health services
Norovirus Acute watery diarrhoea - 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 -

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. Occasionally small intestinal biopsies may be necessary. Eosinophilia may be seen on full blood examination. Mycobacterium avium complex infection may also be associated with chronic diarrhoea – blood cultures are recommended.

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).[14] 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.[15]

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.[16] Pharmacological treatment includes adsorbents (e.g. bismuth), antimotility agents (e.g. loperamide) and antisecretory agents such as octreotide.[17][18] 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.[19]

1.
Antibiotic Expert Groups. Therapeutic guidelines: antibiotic. Version 15. Melbourne: Therapeutic Guidelines Limited; 2014 
2.
Gastrointestinal Expert Group. Therapeutic guidelines: gastrointestinal. Version 5. Melbourne: Therapeutic Guidelines Limited; 2011 
3.
Saag MS, Chambers HF, Eliopoulos GM, Gilbert DN. The Sanford Guide to HIV/AIDS and viral hepatitis therapy. 22 edition. Sperryville: Antimicrobial Therapy Inc; 2014 
4.
Shiboski CH, Patton LL, Webster-Cyriaque JY, et al. The Oral HIV/AIDS Research Alliance: updated case definitions of oral disease endpoints. J Oral Pathol Med 2009;38:481-8 
5.
Saag MS, Chambers HF, Eliopoulos GM, Gilbert DN. The Sanford Guide to HIV/AIDS and viral hepatitis therapy. 22 edition. Sperryville: Antimicrobial Therapy Inc; 2014 
6.
Hamza OJ, Matee MI, Bruggemann RJ, et al. Single-dose fluconazole versus standard 2-week therapy for oropharyngeal candidiasis in HIV-infected patients: a randomized, double-blind, double-dummy trial. Clin Infect Dis 2008;47:1270-6 
7.
Patton LL, Ramirez-Amador V, Anaya-Saavedra G, et al. Urban legends series: oral manifestations of HIV infection. Oral Dis 2013;19:533-50 
8.
Gastrointestinal Expert Group. Therapeutic guidelines: gastrointestinal. Version 5. Melbourne: Therapeutic Guidelines Limited; 2011 
9.
Saag MS, Chambers HF, Eliopoulos GM, Gilbert DN. The Sanford Guide to HIV/AIDS and viral hepatitis therapy. 22 edition. Sperryville: Antimicrobial Therapy Inc; 2014 
10.
Lavery EA, Coyle WJ. Herpes simplex virus and the alimentary tract. Curr Gastroenterol Rep 2008;10:417-23 
11.
Gastrointestinal Expert Group. Therapeutic guidelines: gastrointestinal. Version 5. Melbourne: Therapeutic Guidelines Limited; 2011 
12.
Antibiotic Expert Groups. Therapeutic guidelines: antibiotic. Version 15. Melbourne: Therapeutic Guidelines Limited; 2014 
13.
Saag MS, Chambers HF, Eliopoulos GM, Gilbert DN. The Sanford Guide to HIV/AIDS and viral hepatitis therapy. 22 edition. Sperryville: Antimicrobial Therapy Inc; 2014 
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.
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 
16.
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 
17.
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 
18.
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 
19.
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