November 30, 1999
Gastrointestinal (GI) and hepatobiliary symptoms are ubiquitous in HIV disease. It is estimated that up to 93% of patients will have significant GI symptoms at some point during the course of their HIV illness.1 Further, as HIV progresses and the patient becomes more profoundly immunocompromised, the occurrence of GI symptoms increases.2
GI manifestations in advanced HIV disease result from a wide range of pathogenic etiologies. Those etiologies include protozoan, bacterial, fungal and viral infections; neoplasms such as lymphoma or Kaposi's sarcoma; and idiopathic or poorly defined processes such as "AIDS enteropathy" or apthous ulcerations. At least one study has demonstrated that the presence of intestinal enteropathogens predicts shorter survival in patients with HIV infection.3
This chapter offers information for assessing and treating HIV-positive patients who present with GI symptoms, including the following:
Diarrhea is the most common GI symptom in HIV disease. Studies have documented a prevalence of 504 to 905 percent in persons with advanced HIV infection. Prevalence may vary according to the route of HIV transmission. Centers for Disease Control and Prevention (CDC) studies have shown a higher prevalence of diarrhea in gay men compared to those who acquired HIV through parenteral drug use.6 Some studies have shown a decline in chronic diarrhea since the advent of HAART (highly active antiretroviral therapy), due to a fall in the number of patients infected with opportunistic enteric pathogens.7 Nonetheless, the majority of patients infected with HIV continue to report diarrhea during the course of their illness.
In evaluating a patient with diarrhea, an attempt should first be made to determine the etiology of the diarrhea. A careful history should be taken to determine the following:
When the diarrhea is chronic, an attempt should be made to classify it by pathogenic mechanism: inflammatory (e.g., Crohn's disease, cytomegalovirus [CMV] colitis), osmotic (e.g., pancreatic insufficiency and malabsorption), secretory (e.g., hormone-mediated diarrheas such as carcinoid syndrome), altered intestinal motility (e.g., irritable bowel syndrome) or factitious (laxative abuse).
Medications should be carefully reviewed as a possible cause of the diarrhea, and suspect medications discontinued. A number of HAART medications (especially the protease inhibitors) are commonly associated with diarrhea. Medical records should be reviewed carefully to see if the patient has been diagnosed previously with any enteric opportunistic infections, since symptoms often will be secondary to reactivation of that pathologic process. In addition, medical records can give the palliative care team important insight into the success of previously tried therapies.
Depending on the duration and severity of the diarrhea, it may be appropriate to undertake a limited, noninvasive diagnostic work-up. Stools should be sent for routine culture and sensitivity, acid-fast bacilli culture, ova and parasites and Clostridium dificile toxin. CMV colitis should be considered in patients with advanced immunosuppression (CD4 <50/mm3) and symptoms consistent with that disease (i.e., diarrhea accompanied by low-grade fever and abdominal pain, with or without rebound tenderness). For these patients, an ophthalmologic examination may be advisable, since retinitis often coexists with other end-organ CMV disease. In some cases it may be consistent with palliative principles to perform either colonoscopy or flexible sigmoidoscopy to confirm a suspected diagnosis of CMV colitis, especially now that there exists a welltolerated (though expensive) oral medication (valganciclovir) that can effectively treat CMV end-organ disease without the need for IV access.
Initiation of therapy with limited or no work-up, however, will be appropriate for the majority of patients in advanced AIDS who have diarrhea. If the specific cause of the diarrhea is clearly identifiable, every effort should be made to correct that underlying cause. In many patients, a specific treatable cause will not be found and therapy will need to be empiric and symptomtargeted. In some patients, a brief trial of an antiinfective agent such as an antiparasitic (metronidazole [Flagyl] or paromomycin [Humatin]) or antibacterial may be indicated. For symptom control, antimotility agents such as loperamide (Imodium) or diphenoxylate (Lomotil) or bulk supplements like psyllium should be tried initially.
Two recent abstracts found that diarrhea improved in patients given dietary supplementation with the amino acid L-glutamine or probiotics (acidophilus/bifidobacteria).8, 9 Psyllium and other hydrophilic agents absorb water and can be used to enhance stool consistency. Pancreatic hormone replacement may benefit patients with malabsorption resulting from dysfunction of the exocrine pancreas.
Severe, chronic diarrhea may respond only to opioids such as oral tincture of opium. The usual starting dose is 6 drops (0.6 cc) in two ounces of water every four hours. The dose should then be titrated until symptom control is achieved. There is no maximum ceiling for tincture of opium.
With all of these agents, the patient must always be monitored for the development of constipation or fecal impaction, especially when fluid intake is inadequate. Octreotide (Sandostatin) is a synthetic somatostatin analog that is approved for treatment of profuse water diarrhea secondary to vasoactive intestinal peptide tumors and carcinoid tumors. It has shown variable effectiveness in treating diarrhea in AIDS patients. Its major disadvantages are its high cost and the fact that it needs to be administered subcutaneously on a regular basis.
Intravenous fluids may be appropriate in a patient with dehydration secondary to severe acute or chronic diarrhea. Decisions should be made on a case-by-case basis. If the dehydration is not too severe, oral fluid replacement may be adequate.
In patients known to have a diagnosis of CMV colitis, it may be appropriate to initiate therapy with one of the approved anti-CMV therapies (ganciclovir/Cytovene, foscarnet/Foscavir, cidofovir/Vistide or valganciclovir/Valcyte). Standard induction and maintenance dosing guidelines should be followed. Whereas with CMV retinitis maintenance therapy must continue indefinitely, studies have shown that when treating extraocular CMV disease, maintenance therapy often can be discontinued after a relatively short period of time (usually about four weeks) and the patient simply monitored for signs and symptoms of recurrence.
Dosage information for some drugs used to treat diarrhea is presented in Table 7-1 (PDF).
Though diarrhea is a more frequent problem among end-stage AIDS patients, constipation is also seen. Constipation can sometimes be difficult to determine since there is a wide range of normal bowel habits. Constipation is usually defined as a frequency of bowel movements less than three times a week, but subjective symptoms such as excessive straining, lower abdominal fullness and hard stools must also be considered when making the diagnosis.10 In the palliative care setting, constipation is usually the result of drugs such as opiates that reduce colonic motility and/or of reduced physical activity.
Management of constipation is determined by its severity. Mild constipation can often be treated by increasing the patient's dietary fiber intake to a minimum of 20 to 35 grams daily. Some patients will be able to achieve this minimum by making dietary changes but many will need to take psyllium or another fiber supplement.
If constipation is more severe, treatment with laxatives may be required. A variety of different laxatives can be effectively used, belonging to the following categories:
Table 7-2 (PDF) presents dosage information for a variety of agents discussed above that are used to relieve constipation.
Nausea and Vomiting
Vomiting is under the control of two functionally distinct brain centers. The chemoreceptor trigger zone is found in the fourth ventricle and when stimulated sends impulses to the vomiting center (in the lateral reticular formation) which controls the actual act of vomiting. Management of nausea and vomiting is based on two principal approaches: correcting the underlying causes of the nausea and vomiting, and utilizing appropriate pharmacologic agents to alleviate the symptoms.
With regard to the first approach, the patient's current medications should be evaluated as a possible cause of the nausea and vomiting and any nonessential medications should be eliminated or changed. Special care should be taken to identify those medications known to have a high likelihood of causing nausea and vomiting. A number of medications have been identified as activators of the chemoreceptor trigger zone, including several medications that are frequently used in a palliative care setting such as morphine and other opiates. In addition, several medications used to treat opportunistic infections and other complications of AIDS are known to cause nausea and vomiting in a significant percentage of patients. Those medications include azithromycin (used for treatment and/or prophylaxis of mycobacterium avium complex and cryptosporidiosis), sulfadiazine (used in treatment of toxoplasmosis), zidovudine (sometimes used in a palliative care setting to treat AIDS dementia complex) and a number of other medications.
A thorough physical exam should always be performed to make sure that the patient does not have an acute abdomen. Conditions such as pancreatitis, gastritis and peptic ulcer disease are frequent causes of nausea and vomiting and should be considered in the differential diagnosis. Pharmacologic therapy should be directed both at specific suspected diseases (e.g., H2-antagonists or proton pump inhibitors for gastritis, metoclopramide/Reglan for gastroparesis) and at symptom control with antiemetics. The choice of antiemetic should be based on an understanding of the different classes of medications available and their respective mechanisms of action and therapeutic indices.
Serotonin receptor antagonists are considered highly effective antiemetics with few side effects. They work by selectively binding to 5-hydroxytryptamine3 receptors in the chemoreceptor trigger zone. The American Society of Clinical Oncology has classified these medications as having the highest antiemetic therapeutic index.11 The serotonin antagonists are known to be particularly effective in preventing chemotherapy-induced nausea and vomiting though they have been used effectively in other settings. This class includes ondansetron (Zofran) and granisetron (Kytril).
Substituted benzamides are selective dopamine antagonists that can be useful in all types of vomiting except motion sickness and inner ear dysfunction. Metoclopramide is considered the prototypical medication within this class. In addition to antiemetic effects, metoclopramide also has substantial peripheral cholinergic effects that enhance gastric emptying.10 As such, it can be particularly useful in treating nausea and vomiting secondary to gastroparesis. Gastroparesis is frequently present in patients with AIDS and should especially be considered as a possible etiology in patients who report early satiety or who vomit undigested food more than two hours after a meal. The effectiveness of metoclopramide is limited by its side effects which include acute dystonic reactions, akathisia and sedation.
Butyrophenones (such as haloperidol and droperidol) and phenothiazines (prochlorperazine and thiethylperazine) are less selective antidopaminergic agents with antiemetic activity. They inhibit cerebral dopamine receptors and act primarily at the chemoreceptor trigger zone. Efficacy of these medications is generally lower than that of metoclopramide, and side effects include dystonic reactions, akathisia, sedation and orthostatic hypotension.11
Cannabinoids such as dronabinol (Marinol) exert their effects via the central nervous system and have been found to have antiemetic activity both when used alone and in combination with other medications. Marinol is FDA-approved only for use as an appetite stimulant in AIDS patients (it is approved as an antiemetic for cancer patients receiving chemotherapy) though it has frequently been used "off-label" for management of nausea and vomiting in patients with HIV/AIDS.
The use of adjunctive medications such as glucocorticoids (dexamethasone), benzodiazepines, antihistamines (diphenhydramine, hydroxyzine) or anticholinergics may enhance the effectiveness of antiemetics. Antihistamines and anticholinergics are primarily useful in controlling nausea and vomiting resulting from motion sickness or other inner ear disturbances. They do not act on the chemoreceptor trigger zone and are of little value in other causes of vomiting.10 Antihistamines may be a particularly useful adjunct for patients on phenothiazines or other antidopaminergic medications since they will usually prevent dystonic reactions. H2-receptor antagonists or proton pump inhibitors can be used to control gastritis and gastroesophageal reflux disease, which can also be a cause of nausea or vomiting.
Other interventions that can be tried include changing the patient's diet or giving the patient smaller, more frequent meals until symptoms are under adequate control. If the vomiting is so severe that the patient is unable to take oral medications, the antiemetics should be administered parenterally or by suppository. For patients with chronic nausea, around-the-clock administration of antiemetics should be considered. Finally, appropriate precautions must always be taken to minimize the patient's risk of aspiration.
Table 7-3 (PDF) presents dosage information for many of the antiemetic agents.
Dysphagia and Odynophagia
Prior to the advent of HAART, approximately one-third of AIDS patients at some point developed opportunistic infections involving the esophagus.12 In fact, esophageal symptoms rank second only to diarrhea in frequency of gastrointestinal complaints among patients with AIDS.13 Additionally, since opportunistic disorders of the esophagus usually present only after the CD4 count has dropped to below 100/mm314 they are problems that will frequently be seen in patients who have advanced AIDS.
The most common symptoms of esophageal disorders in persons with AIDS are dysphagia and odynophagia. Less common symptoms are retrosternal chest pain, coughing, and hiccups, which may occur secondary to acid reflux or esophagitis. Those processes may, in turn, lead to aspiration and/or the development of esophageal ulcers that can then heal and leave esophageal scarring.15
Infections are the most common cause of esophageal disorders. The most common infectious etiologies are candida and the herpes viruses herpes simplex (relatively rare) and cytomegalovirus (more common). Mycobacterium tuberculosis and mycobacterium avium complex are infectious causes of esophageal disease that are seen less frequently. Additional etiologies include idiopathic ulcers, apthous ulcers, Kaposi's sarcoma, gastroesophageal reflux disease and pill-induced esophagitis.15
Dysphagia and odynophagia are important symptoms that must be addressed aggressively in the palliative care setting. If inadequately managed, these symptoms will likely cause a significant diminution in the patient's quality of life and lead to other complications such as anorexia, weight loss, malnutrition and the inability to take oral medications. Almost all esophageal infections in patients with AIDS are treatable and in many instances palliation of symptoms will be best achieved by treating the underlying disorder; attempts at symptom amelioration that fail to address the underlying pathology will often be unsuccessful.
Candida albicans is the most frequent esophageal pathogen in HIV disease and, as such, is the most common cause of dysphagia and odynophagia. In evaluating a patient for possible Candida esophagitis, it should be remembered that while the presence of oral thrush supports its presumptive diagnosis, its absence does not exclude it. While definitive diagnosis can be made only with endoscopy, the frequency of Candida infection in advanced AIDS patients makes an empiric trial of antifungal therapy appropriate in these cases.
Treatment requires a systemic antifungal since topical therapies such as nystatin oral suspension or clotrimazole troches only act locally and thus will be effective only in treating oral candidiasis. The medication most frequently chosen to treat Candida esophagitis is fluconazole (Diflucan). The typical treatment course with fluconazole would be to start with a 200 mg loading dose and then to place the patient on 100 mg daily. In many patients a two-week course of therapy will be sufficient to effectively treat Candida esophagitis. Treatment may then be discontinued and the patient observed for recurrence of symptoms. Some patients will require persistent fluconazole therapy and/or doses higher than 100 mg daily. Other medications that can be used to treat Candida are itraconazole (Sporanox) and ketoconazole (Nizoral). If a patient has candidiasis that is resistant to the azoles, it may be necessary to use intravenous medications such as amphotericin-B or the new antifungal caspfungin acetate (Cancidas).
Odynophagia or dysphagia that is caused by CMV infection should be treated with an appropriate course of anti-CMV therapy (see guidelines for treating CMV colitis above). Idiopathic or apthous ulcers can often be effectively treated with either a course of corticosteroids16 or thalidomide.17 Treating odynophagia without regard to the underlying pathology can be attempted by administering standard analgesics or viscous lidocaine but those approaches will often be unsatisfactory. There is no good symptomatic treatment for dysphagia that does not address the causative pathologic process.