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Management Recommendations > Diarrhea

Ward 86 Management Recommendations

Managing HIV Patients with Prolonged Diarrhea

updated January 2019

Contributors: Mark Jacobson, MD
Annie Luetkemeyer, MD
Dan Wlodarczyk, MD

Approach to Diagnosis

Prolonged diarrhea (lasting a week or more) is a common complication of HIV disease. Our approach to determining the cause takes into account the patient's degree of immune suppression. We find it useful to consider a separate differential diagnosis for those whose current absolute CD4 T-cell count is >100 cells/µL. The differential for those with a CD4 count of <100 cells/µL includes the same conditions for those with higher CD4 counts plus several opportunistic infections that occur only with advanced immune suppression.

Information from the patient's history can be helpful in directing the workup. Large stool volumes suggest small intestinal involvement, while small painful stools suggest colonic involvement. The absence of liquid diarrhea excludes Clostridium difficile-associated disease. The presence of blood in stool can be attributed to bacterial pathogens, amebiasis, and cytomegalovirus (CMV) colitis but not to the other pathogens listed below. Fever is not attributable to Giardia, Cryptosporidium, or Blastocystis disease. The patient should be queried regarding recent travel, exposure to farm animals (cryptosporidiosis) or reptiles (salmonellosis), sexual activity (shigellosis), sick contacts, and all recent medications, including herbal medications and immunosuppressants (eg, biologics and chemotherapy) as the latter can cause additional immunosuppression in persons living with HIV. We recommend checking local health department bulletins and the MMWR about recent outbreaks of infectious diarrhea.

If a cause is not found after stool test results are available and Mycobacterium avium complex (MAC) blood cultures (when appropriate) have been obtained, colonoscopy with biopsy should be strongly considered, as diagnoses such as CMV colitis, inflammatory bowel disease, and infiltrative malignancies can be confirmed only by tissue biopsy and histopathologic analysis.

Differential diagnosis of prolonged diarrhea in patients with CD4 count >100 cells/µL

  1. Medications that commonly cause diarrhea include ritonavir and cobicistat (powerful CYP3A4 inhibitors used to boost the blood levels of various antiretroviral drugs), most protease inhibitors, especially lopinavir and darunavir (with nelfinavir, now rarely used, being a significant culprit in the past), many antibiotics (particularly azithromycin, clarithromycin, and clindamycin), and atovaquone.

  2. Infectious causes:

    1. Clostridium difficile-associated disease: This is the most common bacterial cause of prolonged diarrhea in HIV-infected patients.(1) It may occur in absence of recent antibiotic therapy, and can be transmitted outside the health care setting (ie, community acquired). The C difficile toxin assay of stool is a highly sensitive and specific rapid test for making this diagnosis when a liquid stool specimen can be submitted.

    2. Giardia: This protozoan can be transmitted sexually. The traditional stool microscopic exam (O&P) has poor sensitivity. The stool Giardia antigen assay is highly specific but improves sensitivity only to 75%. Because of this diagnostic limitation, we consider treating patients with prolonged diarrhea empirically for giardiasis if all other likely causes have been excluded, and especially if any nonpathogenic, "fellow traveler," protozoan species (eg, Iodamoeba bütschlii, Endolimax nana, Entamoeba coli) are identified in an O&P examination.

    3. Shigella: Shigellosis should be considered in patients with prolonged diarrhea who are sexually active. Symptoms of proctitis or fever may be present. Since 2014, multiple outbreaks of antibiotic-resistant shigellosis among men who have sex with men (MSM) have been observed across the United States.

    4. Blastocystis hominis: It is controversial whether this protozoan is a commensal or a pathogen. However, if B hominis is present in an O&P exam of stool from a patient with prolonged diarrhea in whom other causes have been excluded, we treat the patient as a giardiasis case.

    5. Amebiasis, salmonellosis, and campylobacteriosis may occur but are less common now among HIV patients in the United States than before modern antiretroviral regimens became widely available in the late 1990s. Cryptosporidiosis may occur but is almost always self-limited if the CD4 count is >100 cells/µL.

  3. Noninfectious causes:

    1. Inflammatory bowel disease, particularly Crohn disease, can occur in patients on antiretroviral therapy (ART) whose CD4 count is >250 cells/µL.

    2. Other causes of non-HIV-related diarrhea include malabsorption, chronic pancreatitis, endocrine disorders, biliary disease, celiac disease, lactose intolerance (which can be acquired), irritable bowel syndrome, and small intestine bacterial overgrowth.

Differential diagnosis of prolonged diarrhea in patients with CD4 count <100 cells/µL

In addition to the causes of diarrhea for patients with a CD4 count of >100 cells/µL (listed above), the following should be considered.

  1. Disseminated Mycobacterium avium complex (MAC) infection

    1. Diarrhea is a common manifestation of disseminated MAC, which is a common complication of advanced HIV disease among those who have a CD4 count of <50 cells/µL and are not receiving ART or a MAC prophylaxis regimen.

    2. Fever usually is present.

    3. Mycobacterial blood culture is the gold standard for diagnosis. However, colon or bone marrow biopsy will likely show acid-fast bacteria or poorly formed granulomas.

    4. See section on Disseminated M avium Complex for more information.

  2. CMV colitis

    1. Most cases occur in patients who are not on ART and have a CD4 count of <50 cells/µL.

    2. Fever or hematochezia may be present. Rarely, CMV presents as an acute abdomen due to perforation of the cecum or colon.

    3. Biopsy of colonic mucosa, the gold standard for diagnosis, shows intracellular inclusions typical of CMV. Plasma CMV DNA assays have poor sensitivity and specificity for diagnosis.

    4. Full colonoscopy is required to rule out CMV colitis since nearly half of cases have disease limited to right colon.

    5. See section on Cytomegalovirus Disease for more information including therapy.

  3. Cryptosporidiosis/microsporidiosis

    1. High-volume, watery diarrhea usually is present.

    2. Cholecystitis or cholangitis may be present in cryptosporidiosis.

    3. Special stool stains, such as a modified acid-fast stain, that are highly sensitive and specific can usually make the diagnosis without the need for colonoscopy. However, if stool stain results are negative, the test may need to be repeated with a large volume of stool centrifuged to concentrate the organisms.

    4. There is no highly effective therapy for either of these infections other than immune restoration by ART.

  4. HIV enteropathy

    1. High-volume, watery diarrhea is present.

    2. This is a diagnosis of exclusion and requires colonoscopy to rule out other causes (eg, CMV).

    3. There is no effective therapy other than immune restoration by ART.

  5. Infiltrative malignancies such as lymphoma and Kaposi sarcoma

Approach to Treatment

  • Orthostatic pulse/blood pressure changes should be checked to determine if the patient needs aggressive rehydration.

  • Consider changing ART to a regimen free of protease inhibitors or the ART boosting agents, ritonavir and cobicistat.

  • Review medications for non-HIV-associated agents associated with diarrhea (eg, metformin, over-the-counter magnesium-containing agents).

  • There is an increase in the risk of C difficile and enteric infections in people who take proton-pump inhibitor (PPI) antacids, which cause a reduction in gastric acid, a natural defense against infectious agents. These drugs are commonly used for gastrointestinal complaints and are available without prescription. They also are associated with community-acquired pneumonia and health care-associated pneumonia; malabsorption of iron, calcium, and magnesium; and chronic kidney disease. There are multiple drug interactions between PPIs and antiretrovirals as well. The lowest dosage and the shortest duration of treatment should be used for appropriate indications.

  • Symptomatic relief for ART-related diarrhea. If switching to an ART regimen free of protease inhibitors, ritonavir, or cobicistat is not an option, we use the following stepwise approach:

    1. Take ART pills with food.

    2. Add bulk to stools with oral fiber supplements (eg, oat bran, psyllium).

    3. Loperamide or diphenoxylate/atropine 1-2 tablets taken 1 hour before ART dosing.

    4. Calcium carbonate 500 mg PO BID. Some uncontrolled studies have reported calcium provides relief.(2)

    5. Crofelemer 125 mg PO BID has been approved by the FDA for noninfectious diarrhea in adults on ART. This agent reduces the gut chloride secretion induced by protease inhibitors and boosting agents. However, clinical improvement is modest, and cost is expensive.

  • Symptomatic relief for infectious diarrhea with antiperistaltic agents can be safe unless the patient has severe abdominal pain or signs of sepsis or ileus. It is important that the patient knows to stop taking the medication as soon as the diarrhea becomes tolerable, to avoid constipation. We use loperamide or diphenoxylate/atropine 1-2 tablets Q 2-4 hours until diarrhea decreases.

Empiric antimicrobial therapy

  • C difficile disease

    1. When C difficile is suspected, we avoid empiric antibiotics that can exacerbate C difficile, including quinolones. Any antibiotic that is precipitating C difficile overgrowth should be discontinued, if feasible. Continuing an inciting antibiotic during treatment for C difficile disease has been associated with lower cure and higher recurrence rates.

    2. Choice of therapy for established C difficile disease depends on the severity of the presenting disease. For mild disease, oral metronidazole generally is sufficient. (When prescribing metronidazole, the patient should be advised not to drink alcohol due to the adverse interaction between the two.)

    3. For more severe disease (eg, elevated white blood cell count, fever, new renal failure, concern for clinical stability), oral vancomycin is preferred, in conjunction with supportive care.(3) We consider administering vancomycin by enema or metronidazole intravenously if the patient is severely ill or if ileus is present. Fidaxomicin also is an effective therapy and may reduce the risk of relapse for some strains, but access to the drug has been limited by cost at many centers.(4)

    4. Because the relapse rate of C difficile colitis is high, even when inciting antibiotics are eliminated, there may be a role for probiotics in reducing recurrence; however, live probiotics such as Saccharomyces should be avoided in patients with very low CD4 cell counts.

    5. For patients with recurrent disease, a long-tapering course of oral vancomycin, pulsed-dose vancomycin therapy, or fecal transplantation should be considered, in consultation with an infectious disease specialist. Another, recently available, option is a preventive infusion of monoclonal antibodies that target C difficile toxins, such as bezlotoxumab.(5)

  • Shigellosis

    1. Outbreaks of antibiotic-resistant shigellosis among MSM have been observed across the United States since 2014. Quinolone, ceftriaxone, and azithromycin resistance are being observed at high frequencies in these MSM-specific outbreaks.(6) A stool specimen for culture and antibiotic sensitivity testing always should be obtained when Shigella is suspected, particularly in MSM.

    2. Because San Francisco recently has observed a cluster of cases involving Shigella sonnei that is resistant to both quinolones and azithromycin, we now recommend that local providers not initiate empiric antibiotic therapy for patients with known or suspected shigellosis who are medically stable and/or improving. Appropriate antibiotic therapy can be initiated for such patients if susceptibility testing reveals sensitivity to an orally bioavailable medication. For more seriously ill patients who merit immediate empiric treatment, intravenous ceftriaxone is recommended; however, treatment may need to be changed once results of stool culture antibiotic-sensitivity testing become available.

  • Amoeba, Giardia, B hominis infection

    1. Metronidazole is effective treatment for diarrhea caused these organisms.

    2. Some experts recommend single-dose tinidazole for giardiasis, based on data from randomized trials in children with giardiasis who were not HIV infected.

    3. When prescribing metronidazole, the patient should be advised not to drink alcohol due to the adverse interaction between the two.

  • Diarrhea due to disseminated MAC infection

    Since diarrhea can be a major clinical manifestation of disseminated MAC, we have a low threshold for initiating combination antimycobacterial therapy to cover MAC while awaiting results of mycobacterial blood cultures in at-risk symptomatic patients with CD4 counts of <50 cells/µL (see section on Disseminated M avium Complex for more information).

  • Cytomegalovirus colitis

    Neither ganciclovir nor valganciclovir therapy should be initiated for a patient suspected of having CMV colitis until the diagnosis has been confirmed by colon biopsy (see Cytomegalovirus Disease for more information).

  • Cryptosporidiosis

    1. Immune restoration with ART is the only effective treatment.

    2. For symptomatic relief, we use the following stepwise approach:

      1. First line: loperamide or diphenoxylate/atropine PO 1-2 tablets Q 2-4 hours PRN diarrhea
      2. Second line: tincture of opium 0.4 mg/mL, 5-10 mL QID PRN diarrhea
      3. Third line: A metaanalysis of nitazoxanide and paromomycin treatment trials for cryptosporidiosis in immunocompromised patients has shown a nonsignificant trend toward reduction in the duration and frequency of diarrhea.(7) Nitazoxanide led to significant cryptosporidia clearance in stool compared with placebo, but not among patients with HIV. There is anecdotal evidence that octreotide may be beneficial while waiting for immune restoration to occur on ART.(8)
  • Microsporidiosis

    1. ART-induced immune reconstitution is the only effective treatment.

    2. For symptomatic relief, we use the following stepwise approach:

      1. First line: loperamide or diphenoxylate/atropine 1-2 tabs Q 2-4 hours PRN diarrhea
      2. Second line: tincture of opium 0.4 mg/mL, 5-10 mL QID PRN diarrhea
      3. Third line: There is anecdotal evidence that albendazole or octreotide may be beneficial while waiting for immune restoration to occur.(8,9)
  • HIV enteropathy

    1. ART-induced immune reconstitution is the only effective treatment.

    2. For symptomatic relief, we use the following stepwise approach:

      1. First line: loperamide or diphenoxylate/atropine 1-2 tabs Q 2-4 hours PRN diarrhea
      2. Second line: tincture of opium 0.4 mg/mL, 5-10 mL QID PRN diarrhea
      3. Third line: Octreotide may be beneficial while waiting for immune restoration to occur.


  1. Sanchez TH, Brooks JT, Sullivan PS, et al; Adult/Adolescent Spectrum of HIV Disease Study Group. Bacterial diarrhea in persons with HIV infection, United States, 1992-2002. 2005 Dec 1;41(11):1621-7.
  2. Turner MJ, Angel JB, Woodend K, et al. The efficacy of calcium carbonate in the treatment of protease inhibitor-induced persistent diarrhea in HIV-infected patients. HIV Clin Trials. 2004 Jan-Feb;5(1):19-24.
  3. Stevens VW, Nelson RE, Schwab-Daugherty EM, et al. Comparative effectiveness of vancomycin and metronidazole for the prevention of recurrence and death in patients with Clostridium difficile infection. JAMA Intern Med. 2017 Apr 1;177(4):546-53.
  4. Mullane KM, Miller MA, Weiss K, et al. Efficacy of fidaxomicin versus vancomycin as therapy for Clostridium difficile infection in individuals taking concomitant antibiotics for other concurrent infections. Clin Infect Dis. 2011 Sep;53(5):440-7.
  5. Wilcox MH, Gerding DN, Poxton IR, et al; MODIFY I and MODIFY II Investigators. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017 Jan 26;376:305-17.
  6. Bowen A, Grass J, Bicknese A, et al. Elevated risk for antimicrobial drug-resistant Shigella infection among men who have sex with men, United States, 2011-2015. Emerg Infect Dis. 2016 Sep;22(9):1613-6.
  7. Abubakar I, Aliyu SH, Arumugam C, et al. Treatment of cryptosporidiosis in immunocompromised individuals: systematic review and meta-analysis. Br J Clin Pharmacol. 2007 Apr;63(4):387-93.
  8. Cello JP, Grendell JH, Basuk P, et al. Effect of octreotide on refractory AIDS-associated diarrhea. A prospective, multicenter clinical trial. Ann Intern Med. 1991 Nov 1;115(9):705-10.
  9. Blanshard C, Ellis DS, Tovey DG, et al. Treatment of intestinal microsporidiosis with albendazole in patients with AIDS. AIDS. 1992 Mar;6(3):311-3.