Managing Nausea, Vomiting, and Diarrhea

People with HIV/AIDS frequently experience symptoms that affect the gastrointestinal (GI) tract, made up of the oral cavity (mouth), esophagus (swallowing tube), stomach, intestines, and anus. The most common of these are nausea, vomiting, and diarrhea. Nausea refers to queasiness, feeling sick to the stomach, or having an urge to vomit, or "throw up." Diarrhea refers to frequent, loose, unformed stools (bowel movements). Both may be accompanied by abdominal cramps. Nausea and diarrhea are not diseases themselves, but rather are symptoms that may be caused by a wide variety of conditions. Both are common in the population at large, but occur more frequently and may be more severe in people with HIV/AIDS.

Most people with HIV/AIDS experience nausea and diarrhea at some point during the course of their illness. Roughly one-third of people infected with HIV develop acute retroviral syndrome (ARS), a flu-like illness, one to three weeks following exposure to the virus; nausea and diarrhea are among the symptoms associated with ARS. At later stages of HIV disease, once the immune system is compromised and CD4 cell counts fall below 200 cells/mm³, people are susceptible to a range of opportunistic illnesses (OIs), several of which can cause nausea and diarrhea. Today, however, as improved combination antiretroviral treatment has reduced the incidence of OIs, adverse reaction to drugs is the most common cause of nausea, vomiting, and diarrhea in people with HIV/AIDS.

Of all the symptoms of HIV disease and the side effects of the drugs used to treat it, nausea, vomiting, and diarrhea are among the most distressing. Not only do they limit daily activities and have a detrimental effect on quality of life, they can also compromise an individual's health by interfering with nutrition and medication regimens.

Nausea and Vomiting

Often, nausea and vomiting are signs that the stomach is irritated and trying to rid itself of something it finds disagreeable. This may be caused, for example, by excessive alcohol consumption, overeating, or consumption of contaminated food or water. Many different pathogens (infectious micro-organisms) attack the GI tract and can cause nausea and vomiting (see "Pathogens that Cause Nausea, Vomiting, and Diarrhea," below). In other cases, nausea is less directly related to the stomach itself; for example, in some people nausea accompanies migraine headaches, and women often experience nausea (morning sickness) during the first trimester of pregnancy due to hormonal changes. Other possible causes of nausea and vomiting include head injury or brain damage (affecting the brain's vomiting center), inner ear disorders, intestinal obstructions, liver disease (e.g., hepatitis, cirrhosis), pancreas dysfunction, myocardial infarction (heart attack) or congestive heart failure, endocrine disorders (e.g., diabetes), motion sickness, and emotional stress. In people with HIV/AIDS, nausea and vomiting are common side effect of many of the drugs used to treat HIV and associated conditions (see "Nausea, Vomiting, and Diarrhea as Drug Side Effects," below).

Nausea and vomiting are often transient and resolve on their own. However, severe or persistent vomiting can cause dehydration, electrolyte loss, malnutrition, and weight loss (see "Dangers of Vomiting and Diarrhea," below). Also, with prolonged vomiting the stomach acid in the vomitus can irritate the tissues of the esophagus and cause tooth damage. People should consult a health-care provider if they experience the following symptoms:

• persistent and repeated vomiting lasting for a 24-hour period or longer (less in young children)
• presence of blood in the vomit (vomitus may be bright red or resemble coffee grounds)
• vomiting accompanied by high or persistent fever, severe or prolonged abdominal pain, dizziness, or jaundice (yellowing of the skin and whites of the eyes, dark urine)
• inability to take necessary medications.

In order to treat nausea and vomiting, the underlying causes must be determined; however, measures to relieve symptoms may begin before the cause is known. Health-care providers typically will ask about the severity, frequency, timing (e.g., after meals or when the stomach is empty), and duration of nausea and vomiting, as well as what medications patients are taking and whether they are experiencing additional symptoms.

An upper GI series is a set of x-rays of the esophagus, stomach, and part of the small intestine; in this procedure, a person swallows a barium solution to make the organs more clearly visible. This test may be used to detect blockages, ulcers, and other problems. Endoscopy is the insertion of a flexible, lighted instrument through the esophagus to view the interior of the GI tract. In more complicated cases other tests may be done, including computed tomography (CT) scans, magnetic resonance imaging (MRI), and ultrasound. In addition, a physician may request laboratory tests to evaluate liver, gallbladder, kidney, and pancreas function. If an ulcer is suspected, a Heliobacter pylori bacteria blood test should be done.

Diarrhea

Diarrhea is one of the most common complaints of people with HIV/AIDS, occurring in at least 50% of cases. It is more common in people with advanced HIV disease. Diarrhea typically is defined as two or more loose stools per day. However, what can be considered diarrhea depends on a person's usual bowel habits; some people normally have more frequent or more loose stools than others.

Enteritis is inflammation of the small intestine; gastroenteritis refers to inflammation of both the stomach and the small intestine. Colitis is inflammation of the large intestine (colon). Normally when food is digested, nutrients are absorbed in the small intestine and water is absorbed in the colon, leaving a well-formed stool. Diarrhea occurs when water absorption is disrupted, when too much fluid is secreted into the intestines, or when digested food moves too quickly through the colon to allow proper extraction of water. Diarrhea may be due to problems in the small or large intestine. Small intestine diarrhea is typically higher volume (about two liters per day), while large intestine diarrhea is generally lower volume (about one-half liter per day).

Diarrhea may be caused by microorganisms (see "Pathogens that Cause Nausea, Vomiting, and Diarrhea," below), food intolerances or allergies, chronic bowel disorders (including inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, ulcerative colitis, and celiac disease), and emotional stress. Many people experience diarrhea, cramps, and intestinal gas as a result of lactose intolerance, caused by the lack of an enzyme (lactase) required to digest lactose, a sugar found in milk; the condition is more common in people of African and Asian descent. Diarrhea also sometimes occurs when a person takes antibiotics that kill off normal intestinal bacteria.

People with HIV/AIDS may have diarrhea related to any of these causes. In addition, diarrhea is a frequent side effect of antiretroviral drugs (see "Nausea, Vomiting, and Diarrhea as Drug Side Effects," below) and people with advanced HIV disease may have OIs that cause diarrhea. In some people with HIV/AIDS, diarrhea has no obvious specific cause and is attributed to HIV enteropathy, or intestinal disease caused by the virus itself (possibly related to HIV infection of intestinal lymphatic tissues or damage to the microvilli lining the intestines).

Improper digestion and absorption of fats also can cause diarrhea. A study by Michael A. Poles, MD, of the University of California at Los Angeles (UCLA) Medical Center and colleagues found evidence of fat malabsorption in 30 of 33 HIV positive persons with diarrhea evaluated between 1995 and 1999; the rates of malabsorption were similar in people receiving combination regimens containing a protease inhibitor (PI) and those taking only nucleoside reverse transcriptase inhibitors (NRTIs). According to Dr. Poles, "Fat malabsorption is probably a significant cause of diarrhea in these patients, certainly worthy of an attempt at diagnosis and treatment." Often fat malabsorption is associated with pancreatic disease (the pancreas is a digestive organ that produces enzymes that help digest fats). However, the researchers did not find evidence of pancreatic disease in their study participants, and Dr. Pole suggested that antiretroviral drugs may have had a detrimental effect on fat absorption.

Diarrhea may be either short term (acute) or long term (chronic). Acute diarrhea can lead to dehydration, while prolonged diarrhea can result in malabsorption of nutrients from food, leading to weight loss and possibly severe wasting (see "Dangers of Vomiting and Diarrhea," below). People should consult their physicians if they experience:

• diarrhea lasting more than three days (less in young children)
• diarrhea containing pus or blood (bloody stool may appear black or "tarry")
• diarrhea containing fat, or steatorrhea (stool is foul-smelling and may appear "greasy" and float)
• a change in diarrhea frequency, volume, appearance, or odor
• diarrhea accompanied by high or persistent fever, severe or prolonged abdominal pain, dizziness, or jaundice
• weight loss of more than five pounds or two kilograms.

Like nausea, diarrhea is a symptom, and the underlying cause (or, often, causes) must be determined in order to treat it appropriately. Physicians typically will ask patients about possible exposure to pathogens, frequency and length of diarrhea, normal bowel habits, and additional symptoms. Often a stool sample is taken to determine what type of microorganism or parasite, if any, is responsible. Blood or urine laboratory tests also may be conducted (sometimes microorganisms can be detected in the blood but not the stool).

As with nausea, x-ray tests may be done, although in this case barium is administered as an enema (by rectum) rather than swallowed. Endoscopic tests may be conducted in order to view the interior of the intestines; a colonoscopy is a procedure for viewing the entire large intestine by means of a lighted instrument inserted through the anus, while a sigmoidoscopy examines just the lower part of the colon. Physicians may take a biopsy sample of the intestinal lining to examine for pathogens, cell abnormalities, or tissue damage.

In as many as one-third of cases, diarrhea has no apparent cause; sometimes repeated diagnostic testing must be done before the cause(s) can be determined. Dr. Poles, a gastroenterologist (specialist in GI medicine), recommends a repeat gastrointestinal evaluation every six months if a cause was not found on the first attempt and diarrhea persists.

Pathogens that Cause Nausea, Vomiting, and Diarrhea

Common GI Pathogens

A wide variety of microorganisms -- bacteria, parasites, viruses, and fungi -- can cause nausea, vomiting, and diarrhea (see sidebar). These range from common bacteria and parasites that often cause food poisoning and traveler's diarrhea in the population at large, to opportunistic pathogens that typically cause disease only in people with compromised immune systems.

Food poisoning, which can lead to both vomiting and diarrhea, is caused by food or water contaminated with microorganisms or toxins. Most pathogens that cause diarrhea are transmitted by the fecal-oral route (from feces to mouth), often due to improper hygiene when handling food. Traveler's diarrhea is a common name for food poisoning contracted while traveling, especially in developing countries with poor sanitation systems. (See sidebar for tips on preventing GI infections.) While food poisoning and traveler's diarrhea are common in the general population, people with HIV/AIDS who have weakened immune systems are more likely to become ill due to food- and water-borne pathogens and also are more likely to develop bacteremia or septicemia (bacteria and/or bacterial toxins in the bloodstream). Although vomiting and diarrhea due to infection often clear up spontaneously within a few days, they may be more persistent and require treatment, especially in immunocompromised people.

The most common bacterial food poisoning culprits are Salmonella species (one of which, S. typhi, causes typhoid fever), Shigella species, Campylobacter jejuni, and Escherichia coli (especially the O157:H7 strain). People with bacterial GI infections typically have abdominal pain and watery diarrhea. Dysentery is a more severe form of infectious diarrhea associated with bloody or pus-filled discharge and usually accompanied by fever. Bacterial GI infections are treated with a variety of antibiotics; if the specific cause is unknown, some physicians treat presumptively with a wide-spectrum drug such as ciprofloxacin (Cipro) or TMP-SMX (Bactrim, Septra).

Antibiotic drugs themselves can promote the development of diarrhea caused by a toxin-producing bacteria called Clostridium difficile. This bacteria can proliferate when antibiotics kill off the friendly flora (naturally occurring organisms) that normally live in the intestines and keep harmful organisms in check. C. difficile infection usually is treated with metronidazole (Flagyl) or vancomycin (Vancocin), and other antibiotics are discontinued if possible.

Two common protozoan parasites transmitted by contaminated food and water are Giardia lamblia and Entamoeba histolytica (the cause of amoebic dysentery). Giardia lives in animals as well as humans, and may be present in streams and rivers far from human habitation. Both Giardia and amoebas can be transmitted through oral/anal sex or other contact with feces during sexual activity. Unlike many bacterial GI infections, Giardia can last for months or longer, even in people with healthy immune systems. The usual treatment for giardiasis is metronidazole; this drug should not be taken with alcohol, including medications such as liquid ritonavir (Norvir) that contain alcohol. Amoebas usually are treated with paromomycin (Humatin) and/or iodoquinol (Yodoquinol).

Viral GI infections (e.g., adenovirus, astrovirus, rotavirus) often cause symptoms such as fever, aches, and other flu-like symptoms in addition to nausea and diarrhea-thus the common misnomer "stomach flu." They occur most often in children and immunocompromised people. These viral infections typically are not treated and are allowed to run their course; however, adequate hydration is necessary while diarrhea persists.

Opportunistic Pathogens

People with late-stage HIV disease and compromised immune systems are susceptible to several opportunistic pathogens that can cause diarrhea, including Mycobacterium avium complex (MAC), Cryptosporidium parvum, and cytomegalovirus (CMV). In fact, these OIs are responsible for some of the classic symptoms of AIDS (e.g., night sweats, severe wasting) frequently seen in the early years of the epidemic. These illnesses typically occur when a person's CD4 cell count falls below 100 cells/mm³. The incidence of AIDS-related OIs has fallen dramatically with the widespread use of effective combination antiretroviral therapy. Often if people's CD4 cell counts rise above 200 cells/mm³ with antiretroviral therapy, their immune systems are again able to control the pathogens.

MAC is caused by atypical bacteria and usually occurs in people with fewer than 50 CD4 cells/mm³. Symptoms include fever, night sweats, abdominal pain, diarrhea, and wasting. Recommended treatment for MAC is a combination regimen of at least three drugs, including either azithromycin (Zithromax) or clarithromycin (Biaxin). Primary prophylaxis with azithromycin, clarithromycin, or rifabutin (Mycobutin) is recommended to prevent a first episode of MAC in people with fewer than 50 CD4 cells/mm³. Long-term maintenance therapy to prevent recurrence is also recommended.

Opportunistic protozoan parasites include C. parvum (which causes cryptosporidiosis), Cyclospora cayetanensis, Isospora belli, and the microsporidia species Enterocytozoon bieneusi and Encephalitozoon (Septata) intestinalis.

Cryptosporidiosis, which is transmitted through contaminated food and water (including tap water in some cities), is characterized by abdominal cramps, diarrhea, and wasting. People with fewer than 200 CD4 cells/mm³ may experience prolonged infection. Cryptosporidiosis cannot be cured, but may be treated with paromomycin and/or azithromycin; despite promising studies, in 1998 the U.S. Food and Drug Administration (FDA) declined to approve the experimental drug nitazoxanide (Cryptaz) for this indication.

C. cayetanensis and I. belli are treated with TMP-SMX or ciprofloxacin, and maintenance therapy may be needed. A variety of different medications may be used to treat microsporidiosis (including E. bieneusi and E. intestinalis), including albendazole (Albenza), atovaquone (Mepron), fluconazole (Diflucan), metronidazole, pyrimethamine (Daraprim), and TMP-SMX.

CMV is best known as a virus that attacks the eyes, leading to retinitis (inflammation of the retina) and blindness. However, it also can affect the GI tract, causing esophagitis (inflammation of the esophagus) and colitis. CMV colitis is characterized by ulceration of the lining of the colon. Symptoms may include anorexia (loss of appetite), fever, and abdominal cramps in addition to diarrhea. Although CMV infection is very common, the virus usually only causes symptomatic illness in people with fewer than 50 CD4 cells/mm³. CMV colitis may be treated with intravenous cidofovir (Vistide), foscarnet (Foscavir), or ganciclovir (Cytovene); in March 2001 an oral drug called valganciclovir (Valcyte) was approved (see "Valganciclovir" in the Winter 2002 issue of BETA).

Fungal pathogens rarely cause diarrhea. An exception is Histoplasma capsulatum, an atypical fungus that infects the colon and can cause fever, abdominal pain, diarrhea, and weight loss. Treatments include itraconazole (Sporanox) and amphotericin B (Fungizone).

Nausea, Vomiting, and Diarrhea as Drug Side Effects

Nausea, vomiting, and diarrhea are the most common GI toxicities, or side effects, associated with antiretroviral medications. Others include esophagitis, acid reflux ("heartburn"), intestinal gas (flatulence), abdominal cramps, abdominal bloating, and constipation. Although anti-HIV drugs may directly irritate the lining of the GI tract, studies suggest that the drugs actually cause nausea, vomiting, and diarrhea because the body regards them as toxins and tries to eliminate them. In addition, some antiretroviral drugs increase intestinal transit time, causing food to pass more quickly through the intestines and not allowing sufficient time for water to be absorbed by the colon.

The occurrence of nausea and diarrhea as drug side effects varies widely among individuals. Some people experience these symptoms frequently, while others experience them rarely or never. Severity also varies widely. People with late-stage HIV disease are prone to more severe symptoms, but people at any stage of disease may experience nausea and diarrhea as a side effect of medications.

Drug side effects can have a major detrimental effect on quality of life and on medication adherence. Andrea Tramarin, MD, from the Civil Hospital of Vicenza, Italy, and colleagues reported at the 11th European Congress of Clinical Microbiology and Infectious Diseases in April 2000 that among people with HIV receiving antiretroviral treatment, those who experienced severe or moderate diarrhea reported a significantly impaired quality of life compared with those without diarrhea. A 1998 study by researchers at the University of California at San Francisco (UCSF) Center for AIDS Prevention Studies found that concern about side effects was a major factor deterring people from starting antiretroviral treatment. Nausea, vomiting, and diarrhea also can discourage people from taking their drugs once they have started. This is especially true for people with early-stage HIV disease who felt healthy and experienced few or no symptoms before starting therapy; not surprisingly, some of these people may come to believe that they are better off without the drugs.

Nausea, vomiting, and diarrhea associated with antiretroviral medications often subside once the body becomes accustomed to the drugs. In many cases, symptoms are most severe when a new medication is started and for four to six weeks thereafter. (In general, if a new case of nausea or diarrhea develops in the absence of a recent change in medication, it is probably not a drug side effect.) During this initial period, dietary measures and antinausea or antidiarrhea medications may help control symptoms. With some drugs, side effects can be controlled by starting with a small dose that is gradually increased (desensitization). If a drug does not have to be taken on an empty stomach, taking it with food may help reduce nausea. People experiencing drug-related nausea or diarrhea should consult their physicians about possible desensitization and the proper timing of medications with food.

Uncommonly, nausea and diarrhea do not decrease with time, necessitating changes to a person's drug regimen. It can be difficult to determine which medication in a combination regimen is responsible, especially if multiple drugs were started at the same time. Sometimes dose reduction or splitting drug doses and taking them more often during the day is possible. Different people react differently to medications, and in many cases another drug from the same class can be substituted. Because of the risks of suboptimal dosing (including increased viral load and the development of drug-resistant HIV), people who experience persistent GI side effects should consult their physicians and should not attempt to adjust their drug regimens themselves.

Ultimately, each person with HIV must weigh the benefits and risks of treatment for himself or herself. For many, the benefits of controlling the virus will outweigh negative drug side effects. Others-especially those with early-stage HIV infection who have few or no symptoms-may decide that remaining free from persistent GI distress is more important to them.

Drugs that Cause GI Side Effects

All currently approved NRTIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs), and PIs are known to cause nausea, vomiting, or stomach upset, and all PIs are known to cause diarrhea. However, certain drugs are associated more often with specific symptoms. For example, among PIs, nelfinavir (Viracept) and Kaletra (lopinavir/ritonavir) most often cause diarrhea, although the diarrhea associated with full-dose ritonavir tends to be more severe. Among the NRTIs, ddI (Videx) has been most associated with diarrhea, although GI side effects are less of a problem with the new enteric-coated formulation (Videx EC). As noted previously, GI symptoms related to antiretroviral therapy typically decrease over time.

Severe nausea and diarrhea are among the symptoms of the potentially fatal hypersensitivity reaction that occurs in 3-5% of people taking abacavir (Ziagen) or Trizivir (AZT/3TC/abacavir). Persons who experience these symptoms (or fever, abdominal pain, sore throat, shortness of breath, or skin rash) should seek immediate medical care.

GI symptoms also are associated with drugs used for a range of other conditions seen in people with HIV/AIDS, including cidofovir, foscarnet, and ganciclovir, all used to treat CMV; interferon-alpha, used to treat chronic hepatitis B and C; rifampin (Rifadin, Rimactane) and ribafutin, both used to treat tuberculosis and MAC; fungal medications including fluconazole, ketoconazole (Nizoral), and itraconazole; and certain narcotic pain medications (e.g., codeine, morphine). Most cancer chemotherapy agents cause nausea because they target rapidly growing cells, including those lining the stomach. Many antibiotics can cause diarrhea by killing off beneficial flora in the intestines and allowing the overgrowth of C. difficile.

Dangers of Vomiting and Diarrhea

Vomiting and diarrhea are not only unpleasant and restrictive of daily activities, but also can interfere with the proper absorption of water, food, and medications, potentially leading to dehydration, disruptions in body chemistry, malnutrition, weight loss, and inadequate drug levels.

Dehydration, or an inadequate amount of water in the body, is one of the most serious potential consequences of vomiting and diarrhea because it can lead to shock and even death within a short period of time. People can go without water for only a few days, and even less if the body's fluids are actively being lost; people with severe diarrhea may lose as much as a gallon of water in a day. Dehydration can be especially dangerous in the elderly and in children; in fact, dehydration related to diarrhea is one of the most common causes of death for children in the developing world.

The symptoms of dehydration include:

• thirst
• dry mouth, tongue, and throat
• fatigue
• anxiety or irritability
• light-headedness or fainting, especially when standing up
• decreased urination
• dark yellow or orange urine (may resemble tea)
• increased heart rate
• sunken eyes
• dry skin
• loss of skin elasticity (failure of the skin to flatten after being pinched)
• muscle weakness
• confusion
• fever

Along with water, people with vomiting or diarrhea also lose electrolytes (minerals), especially sodium, potassium, magnesium, and chloride. Electrolytes are crucial for many bodily functions, and electrolyte imbalances can be life-threatening. For example, loss of chloride due to prolonged vomiting can lead to a condition called metabolic alkalosis, characterized by mental confusion and muscle spasms.

People with vomiting and diarrhea should immediately replace lost fluids by drinking. Because they contain important nutrients, sugars, and electrolytes, fruit juices, broth, energy or sports drinks (e.g., Gatorade), and ginger ale often are recommended over water. Bananas are a good source of potassium, and most soups contain sodium. Alternatively, an oral rehydration solution can be prepared by mixing a teaspoon of salt and eight teaspoons of sugar in a liter of water; rice water is also widely used for rehydration. Sip fluids slowly to avoid triggering further vomiting or diarrhea. Avoid drinks that contain caffeine, because caffeine is a diuretic that can cause further fluid loss due to increased urination. Oral rehydration usually can counteract the loss of fluids and electrolytes due to vomiting or diarrhea, but in cases of severe dehydration, intravenous fluids may be necessary.

Diarrhea that continues over a prolonged period of time can cause poor absorption of nutrients, leading to weight loss. Wasting, or involuntary loss of more than 10% of baseline body weight, occurs most often in late-stage HIV disease. Various dietary measures (e.g., commercial formulas such as Advera or Ensure) and medications (e.g., human growth hormone [Serostim], megestrol acetate [Megace],