AIDS TREATMENT NEWS #133, August 23, 1991
Michelle Roland

Much of the frustration of managing GI disease results from the slow and confusing diagnostic process and the uncomfortable medical procedures involved. In this article, we will describe many of the possible causes of various symptoms, and the tests and procedures a doctor would be most likely to recommend in order to make a diagnosis. We hope that this information will serve two purposes. The first is to demystify the doctor's thinking process. The second is to provide people with these symptoms with enough information to be comfortable asking informed questions about the diagnostic and treatment plans. The dialogue which results will be helpful to both the patient and the doctor as they try together to figure out the nature of the problem and the treatment options.

This article is organized into two main sections. ction I describes common symptoms associated with different parts of the GI tract, the organisms or diseases which may cause them, and selected treatment information. In most cases, we do not provide an exhaustive description of standard therapies and experimental treatment options because we reported on much of that information in our opportunistic infections update after the Seventh International Conference on AIDS in Florence (AIDS TREATMENT NEWS #129; June 28, 1991). Instead, we emphasize new information that was not in our Florence report, especially about clinical trials which are open or are being planned. Section II focuses on the specific steps involved in the diagnosis of the most universal problem, diarrhea. We also discuss some approaches to managing diarrhea, and include a brief discussion of nutritional supplementation.

SECTION I:

Diseases of the Esophagus (Esophagitis)

The most common symptoms associated with esophagitis include difficulty swallowing (feeling like food is sticking in the throat), painful swallowing, and/or pain located in the middle of the chest, with or without weight loss. These symptoms can be caused by candida (the organism which causes oral thrush), CMV, herpes, or other less common organisms. KS and lymphoma are unusual in the esophagus, but may occasionally be found there. Aphthous ulcers, the cause of which are unknown, can cause severe oral and esophageal pain in people with HIV. Ulcers may also result from taking certain medications, including AZT, while lying down and without adequate fluids. Recently, a report released by the National Institute for Allergy and Infectious Diseases (NIAID) described a large esophageal ulcer in a man who was taking ddC; it started healing when he stopped taking the drug. It is not clear if ddC caused the ulcer, especially since CMV was found in it. However, if esophageal ulcers develop while taking ddC, and they do not improve with antifungal or acyclovir treatment, it is recommended that ddC be discontinued while diagnostic tests are performed.

People with oral thrush who have a sudden onset of difficulty swallowing most likely have esophageal thrush. It is not usually necessary to do any diagnostic procedures in this case, and treatment with fluconazole (Diflucan) or ketoconazole can be initiated. Because not all people with esophageal thrush also have oral thrush, many physicians will start treating immediately if the only symptom is difficulty swallowing, even in the absence of oral thrush.

When there are additional symptoms, or a course of treatment for thrush is ineffective, two diagnostic procedures may be considered. Endoscopy -- which involves inserting a flexible rubber tube down the throat, observing the esophageal tissue through a lens, and often taking biopsies -- tends to provide the most useful information . However, some people are unwilling or unable to undergo endoscopy. In this case, swallowing barium and taking x-rays (barium studies) may be helpful.

Esophageal herpes can be treated with oral or intravenous (IV) acyclovir. Some lesions may not respond to acyclovir, in which case foscarnet may be helpful. Foscarnet is not yet FDA- approved, so it must be obtained by a physician from the manufacturer, Astra Pharmaceuticals. It will only be provided to patients who have already failed IV acyclovir therapy. For more information, physicians may call Astra at 800/388-4148. [Note that an FDA advisory committee recently recommended that the FDA approve the licensing of foscarnet, so it may soon be available by prescription.]

The standard treatment for CMV is ganciclovir (DHPG, also called Cytovene). Many people require life-long treatment to prevent recurrences of the CMV lesions. Foscarnet may also be available if ganciclovir fails to control esophageal CMV. Sometimes CMV may no longer be found after using ganciclovir, but the lesions may not have healed. Steroids appear to be useful in some of these situations.

Aphthous ulcers (related to canker sores; also known as idiopathic ulcers, which means that the cause is unknown) have been treated in a couple of very small studies with a variety of steroids (oral prednisone, intralesional methylprednisolone acetate, intravenous hydrocortisone, or, for oral ulcers, topical clobetasol proprionate).1,2 In one study, topical tetracycline was used in addition to steroids for oral ulcers.3 Although steroids appear to be effective in reducing the symptoms associated with these ulcers, recurrences are common. (Joseph Sonnabend, M. D., of the Community Research Initiative in New York, has suggested that the prescription drug pentoxifylline (Trental) should be studied to see if it may be useful in treating aphthous ulcers.)

Thalidomide has been anecdotally reported to be effective in the treatment of aphthous ulcers in people with HIV. 4,5,6 Because it causes serious birth defects, thalidomide is not approved for marketing in the United States, and is only being used in the context of clinical trials and for the treatment of Hansen's disease (leprosy). It is manufactured by Pediatric Pharmaceuticals of Westfield, New Jersey. The president of that company, Mr. Robert Stites, explained that he has applied for approval from the FDA to distribute the drug to individual physician investigators who have completed the appropriate paperwork but that approval has not yet been granted. Mr . Stites can be reached by physicians wishing information on the status of FDA approval for individual physician use at 908/225- 0989.

Esophageal ulcers can be caused by taking medication, including AZT, while lying down and without adequate fluids. All medications should be taken with a glass of water or other fluids while sitting or standing. As described above, ddC may also cause esophageal ulceration.

Diseases of the Stomach (Gastritis)

Common symptoms of gastritis include nausea, vomiting (with or without blood), pain or discomfort in the upper abdomen, black/tarry stool (the color and consistency are due to digested blood), and feeling full after eating a small amount of food. It is important to realize that many of the stomach diseases seen in people with HIV infection are not HIV-related, including peptic ulcers and various alcohol-related problems. A type of bacteria commonly seen in HIV-negative individuals with chronic inflammation of the stomach, Helicobacter pylori, is also found in people with HIV; it is not clear if it is more common or more difficult to treat in the context of HIV. The most common HIV- related causes of gastric symptoms include KS, lymphoma, and CMV.

The same diagnostic procedures as described in the section on esophagitis apply to cases of suspected gastritis. Barium studies will show large tumors; endoscopy may be required to get biopsy samples or to see small lesions caused by CMV or other organisms.

Currently available treatment options for CMV infections are described above. A full discussion of standard and experimental KS treatments can be found in AIDS TREATMENT NEWS #122 (March 1, 1991). Lymphoma treatment involves intensive chemotherapy.

Diseases of the Liver, Gall Bladder, and Bile Duct (Hepatobiliary Disease)

The most common symptoms associated with hepatobiliary disease include pain or discomfort in the upper right portion of the abdomen (where the liver and gall bladder are located), fever, nausea, and vomiting. Occasionally diarrhea and/or jaundice (yellowish skin and eyes) may be present. The liver is often enlarged, and liver function tests, especially an enzyme called alkaline phosphatase, are elevated on routine blood tests.

People with HIV can have non-HIV specific gall bladder or liver infections, or blockage of the bile duct, and these should be considered by the physician. The most common HIV-related causes of gall bladder and bile duct disease are CMV and cryptosporidium. The liver can be infected with hepatitis B, tuberculosis (TB), cryptococcus, histoplasma, or MAC . KS and lymphoma may also be found there. Many of the diseases of the liver, gall bladder, and bile duct occur as a part of a disseminated process, meaning they affect more than one part of the body. Therefore, if a person has already been diagnosed with one of these infections or cancers, and has the symptoms listed above, they may be due to the same disease.

Four procedures are commonly employed to diagnose the cause of hepatobiliary disease. Ultrasound and/or CT (CAT scan) are usually the first choice and are non-invasive picture-taking techniques similar to x-rays. When bile duct disease is suspected, it may be necessary to insert an endoscope into the area where the bile duct opens into the small intestine. Dye is injected into the bile duct system so that x-rays can be taken to see if there is inflammation, blockage, or dilation of the ducts. Liver biopsies are rarely required to make a diagnosis of the cause of liver disease. However, when there is no disseminated infection (MAC, KS, lymphoma, CMV, etc.) , the liver enzyme levels remain very high, and the liver enlargement does not decrease, it may be necessary to do a biopsy to see what organism(s) is causing the problem.

Treatment may include surgery in the case of some types of acute inflammation of the gall bladder. Bile duct blockage is often treated by dilating the duct mechanically through an endoscope. A study at San Francisco General Hospital is looking at the use of ursodiol, a drug normally used to treat gall stones, in people with endoscopy- proven bile duct disease who have elevated liver enzyme levels and significant pain in the area of the liver. For more information about this study, call Mary Chan, M. D., or Kristin Weaver, R. N., at 415/821- 8822.

FIAU, an experimental drug which has been found to have too many side effects at doses needed to work against CMV, is now being tested in people with chronic hepatitis B infection. It is believed that lower doses, those with fewer side effects, may be adequate to stop the hepatitis virus from replicating, although it is not known how long treatment might be required. This study is being conducted at the National Institutes of Health (NIH) in Bethesda, Maryland, and at three other sites. Participants must have greater than 200 T-helper cells, liver enzymes (transaminases) no more than five times greater than normal, and be using no other experimental therapies. For more information on this new trial of FIAU in hepatitis B, call:

NIH: 301/496-1836; David Paar, M. D. (Physicians only, please)

University of Washington, Seattle: 206/223-3240; Thomas Hooton, M. D.

University of Calif., San Diego: 619/543-8080, ask for the screening nurse;

University of Alabama, Birmingham: 205/934-5316; Richard Whitley, M. D.

Note that Hepatitis B is a preventable disease. Your doctor can do blood tests to find out if you have ever had hepatitis B. If you have not, you should discuss being immunized with Recombivax, the vaccine which prevents new infection. Also note that alpha interferon is available to treat some cases of hepatitis B.

Diseases of the Small Intestine (Enteritis)

Small bowel disease is usually associated with frequent, large volume diarrhea, abdominal cramping, pain in the area around the belly button, and bloating. Slow weight loss may occur, although the appetite is usually normal. Fever may or may not be present. Lactose intolerance is frequent, resulting in an inability to digest milk products.

These symptoms can be caused by non-HIV specific organisms such as salmonella, shigella, campylobacter, giardia, and Entameba histolytica. The most common HIV-related causes include MAC, cryptosporidium, CMV, Isospora belli, microsporidia, and HIV itself.

The first step in the diagnosis of these symptoms is repeated (at least three, often more) stool samples which are both cultured and examined with a microscope. Viral cultures from rectal swabs are also easy to perform. If no organisms are found in the stool, there is some controversy about which procedure should be done next. Some clinicians would first do a sigmoidoscopy (a scope which is inserted through the anus and rectum and into the last part of the large intestine) or a colonoscopy (this scope is longer and can go further into the colon). Only if these procedures, with biopsies, failed to reveal any organisms in the colon would they then proceed to an endoscopy with collection of fluid and biopsies of the small intestine. Others would do the endoscopy first, especially if they suspected involvement of the esophagus or stomach in addition to the intestines.

The only way to diagnose microsporidiosis is with an electron microscope. A biopsy sample should be sent specifically for this type of study. In addition, special types of stains are required to see some of the other organisms. In laboratories where these stains are not routinely used, the doctor must order them specifically. It might be helpful to discuss which organisms the lab will be looking for, and if any special stains or procedures must be ordered.

There is no standard treatment for cryptosporidiosis, although there are at least two new compounds currently in, or soon to enter, clinical trials. People with this infection have often tried a variety of approaches which have been suggested to be effective in a small number of people. Although some people have experienced symptom improvement and a decrease in the number of organisms found in their stool when using each of these compounds, including paromomycin (Humatin), diclazuril, spiramycin, and hyperimmune bovine colostrum, none of the reports have demonstrated a very high rate of cure or improvement.

566C80, the same drug which is being tested in people with PCP and toxoplasmosis, is also being studied in people with cryptosporidiosis or microsporidiosis at the NIH. This study requires a total of twelve days of hospitalization at the NIH, and approximately eight additional visits to the clinic (every two weeks). Although there is a placebo involved, the design contains a cross-over, so that everyone will receive at least ten weeks of 566C80 and ten weeks of placebo.

In order to be eligible for the study, participants must have an AIDS diagnosis or fewer than 200 T-helper cells. They may not have any infections other than cryptosporidiosis or microsporidiosis which could contribute to their diarrhea (e.g., CMV colitis, MAC, etc.). ddI and ddC will be allowed, but all other investigational agents, including paromomycin, diclazuril, spiramycin, and bovine colostrum, will not be allowed during the study (previous use is okay). Several diagnostic procedures, including endoscopies and colonoscopies, are required. For more information, call Kristin Ownby, R. N., at 800/772-5464 extension 305.

The second new compound is letrazuril, a drug which is related to diclazuril. It is thought that one of the reasons that response to diclazuril is erratic is that the drug is not very well absorbed. It appears that letrazuril will be better absorbed. Investigators both in and outside the AIDS Clinical Trials Group (ACTG) are currently planning clinical trials with letrazuril. It may be several months before these trials open, however. When they do open, information on where they are being conducted and whom to contact will be available by calling 800/TRIALS-A.

Microsporidiosis is a relatively newly recognized opportunistic infection -- unknown until recently because it is difficult to diagnose. There have been anecdotal reports of the use of Flagyl, Bactrim, and pyrimethamine which have suggested some activity. We reported after the Seventh International Conference on AIDS in Florence on the use of an anti-worm drug called albendazole in a very small number of patients in Britain. Since then, we know at least one researcher who will try the drug in a few patients to see if it warrants further study. It is not approved in the United States.

In addition to the 566C80 study described above, some investigators believe clarithromycin and/or azithromycin may be helpful in microsporidiosis. Azithromycin has been shown to be effective in a rat model of microsporidiosis, and a clinical trial is in the early planning stages through the ACTG. A clarithromycin trial, unfortunately, has been delayed for several months. Neither of these drugs is approved in the United States; both may be available through some buyers' clubs (see note in Announcements, below).

Diseases of the Colon (Colitis) and Rectum

In contrast to the large volume diarrhea associated with small bowel disease, colitis is usually associated with very frequent (up to 30 per day), small volume diarrhea, which may contain bright red blood and/or mucus. Mild cramping and lower abdominal pain, a feeling of urgency to have a bowel movement, inability to control the bowel movement (fecal incontinence), and pain with a bowel movement may be present. In some cases, spiking fevers and rapid weight loss can result in significant debilitation.

Common causes of colitis in people with HIV include CMV, cryptosporidiosis, shigella, Entameba histolytica (amebiasis), and campylobacter infection. Herpes, chlamydia, and KS may also rarely cause these symptoms. Non-HIV related ulcerative colitis may be detected. Finally, colitis may result from the use of broad spectrum aonoscopy with biopsies, and occasionally CT or barium contrast studies. Treatments for CMV and cryptosporidiosis have been discussed in previous sections.

Diagnostic procedures include stool samples (at least three), sigmoidoscopy or colonoscopy with biopsies, and occasionally CT or barium contrast studies. Treatments for CMV and cryptosporidiosis have been discussed in previous sections.

Rectal infections including chlamydia, gonorrhea, CMV, or herpes may cause pain in the anus or rectum, discharge with pus, and/or diarrhea. Rectal swabs should be examined. Cancer of the rectum or colon can also occur in HIV-positive individuals and should be considered in the diagnosis of the symptoms discussed in this section.

[Note: There is often significant overlap in symptoms, and they do not always fit into the descriptions presented above.]

SECTION II:

Diagnosing Diarrhea

Almost every person with HIV infection will have to deal with diarrhea. In some cases, the diarrhea may come and go without causing significant problems. However, when diarrhea is causing weight loss, fatigue, or altering your daily activities, you will probably find yourself going to the doctor. We present much of the same information as above, but organize it so that you can think of how your doctor may be considering your symptoms. We also include some information on therapies to control diarrhea and on nutritional management.

Possible Causes

Diarrhea can be caused by a large number of organisms, including the viruses CMV, herpes, adenovirus, or enterovirus; the protozoa cryptosporidium, microsporidium, entameba histolytica, intestinal spirochetes, or Isospora belli; the bacteria MAC, shigella, Campylobacter jejuni, or C. difficile; and the fungi cryptococcus or histoplasma. Diarrhea can also be a side effect of drugs being used for other infections. HIV itself is thought to be responsible for diarrhea in a significant number of patients. Frequently, more than one of the organisms listed above may be involved at a given time.

Diagnostic Approach

Diarrhea can result from infection or cancer (KS or lymphoma) in the small intestine (called upper GI disease or enteritis) or in the large intestine or colon (called lower GI disease or colitis). The specific symptoms (frequency and amount of stool, color, blood or mucus, presence and location of pain, etc.) commonly experienced when the disease is located in these two parts of the GI tract are described in Section I. Some of the organisms can be seen in stool samples, although multiple samples are usually necessary and the doctor must often remember to order special stains or procedures which are not routinely used in the laboratory. There are two kinds of stool samples that a doctor should request: ova and parasites (also called O & P; ova are eggs) and stool cultures.

When no organisms can be isolated from the stool samples, it is often necessary to do a sigmoidoscopy, colonoscopy, and/or endoscopy. These procedures involve inserting a flexible rubber tube with a light and lens at the end, observing the tissue with the naked eye, and taking small pieces of tissue (biopsies) for special staining and examination under a microscope. The sigmoid colon is the last portion of the large intestine before the rectum, thus a sigmoidoscopy looks in the terminal parts of the colon. A colonoscopy involves looking further up the colon, and requires using a longer scope. In both of these cases, the scope is inserted through the anus. The endoscope is inserted through the mouth and into the small intestine. Depending on your specific symptoms, your doctor may recommend starting with the sigmoidoscopy, and, only if nothing is found, moving on to the colonoscopy. Again, if no organisms or cancers are found, an endoscopy may be recommended. Depending on your specific symptoms, an endoscopy might be performed first. Barium enemas or swallows with x-rays are often used to look for problems in the small or large colon as well.

These procedures are not comfortable, although sedating medication makes it easier. They are, however, often crucial in order to make a diagnosis. It is extremely important that physicians who are doing these types of exams remember that often more than one organism is involved; they should not necessarily stop looking for organisms in stool or biopsy specimens after they have found one.

Diarrhea Symptom Control

Clearly, the first choice in managing diarrhea is to treat the underlying cause. However, adequate treatment is not always possible, leaving symptom control as the only option. The drugs used most commonly for the control of diarrhea include Imodium, which is available over the counter, and the prescription drug Lomotil. In addition, some physicians recommend aspirin or aspirin-like compounds (indomethacin, ibuprofen); we have heard that among these, indomethacin may be the most effective. The aspirin-like compounds do have side effects, including ulcers, and so should be used cautiously. Some opiates, like long-acting morphine sulfate, paregoric, and tincture of opium, are sometimes prescribed, although they are addicting and have significant sedative effects.

An injectable drug called Sandostatin has also been helpful in some people, although it is very expensive and not all insurance companies and other third party payers will cover it. There are some on-going clinical trials using Sandostatin. Call 800/TRIALS-A for more information. We have heard that in some cases people stop responding to Sandostatin if too much is being used and that they have to reduce their dose. We have not been able to confirm this observation at press time, but if you are using Sandostatin and it is no longer effective, you may want to talk with your doctor about decreasing the dose.

Nutritional Management

Malnutrition and weight loss can be among the most debilitating consequences of GI disease. Recent studies suggest that even very early in HIV infection, before symptoms appear, people may not absorb normal levels of nutrients from the gut and into the blood stream. In addition to absorbing nutrients, maintaining adequate fluid and chemical (electrolyte) levels can also be a critical problem with frequent or large volume diarrhea. It is essential that these issues be addressed in the medical management of any person with GI symptoms, especially diarrhea and vomiting.

Doctors differ in their treatment of absorption problems. Some recommend large doses of vitamins and minerals. Others worry that some of these may be useless, or worse, harmful when used in very high doses. However, everyone seems to agree that the area of nutrition and nutritional supplementation is critically important and vastly understudied. We plan to publish information on nutrition in upcoming issues of AIDS TREATMENT NEWS.

In standard medical practice, there are two ways to approach weight loss. The first is to stimulate the appetite. Some people find marijuana to be useful for this purpose; a legal drug, called Marinol (dronabinol) contains the active ingredient, and is available by prescription and in clinical trials. A drug called megace has been used in people with cancer, and recent studies in people with AIDS suggest that it is an effective appetite stimulant, often resulting in weight gain and an improved sense of well-being. Megace is also available by prescription.

The second approach is to supplement the usual diet with liquid food. Sometimes these supplements are in the form of canned drinks (they have names like Ensure and Sustecal). Oral supplements are most helpful in people who are still able to absorb nutrients from the GI tract. Some new formulations are currently being tested in clinical trials.

In more serious cases of malabsorption, liquid food can be delivered intravenously. Unfortunately, this requires surgical placement of tubing (a catheter) into a large vein in the chest which empties directly into the heart. Nutritional supplements given through such a "central line" are called TPN, or total parenteral nutrition; parenteral means not oral. Although TPN is very expensive, and using it is inconvenient and requires training, it can significantly extend the life of someone who is wasting as a result of chronic diarrhea, loss of appetite, and/or malabsorption.

References

1. Borcich A, Reka S, Winkler W, and Kotler D. Corticosteroid therapy of idiopathic esophageal ulcers in AIDS. Sixth International Conference on AIDS, June 1990, abstract #Th.B. 361.

2. Bach M, Howell D, Valenti A, Smith T, and Winslow D. Aphthous ulceration of the gastrointestinal tract in patients with the acquired immunodeficiency syndrome (AIDS). Annals of Internal Medicine. March 15, 1990; volume 112, number 6, pages 465-467.

3. Phelan JA, Eisig S, Freedman PD and others. Major aphthous- like ulcers in patients with AIDS. Oral Surgery, Oral Medicine and Oral Pathology. January 1991; volume 71, number 1, pages 68-72.

4. Youle M, Clarbour J, Farthing C, and others. Treatment of resistant aphthous ulceration with thalidomide in patients positive for HIV antibody. British Medical Journal. February 18, 1989; volume 298, number 6671, page 432.

5. Nicalou D and West T. Thalidomide: treatment of severe recurrent aphthous stomatitis in patients with AIDS. DICP, The Annals of Pharmacotherapy. November, 1990; volume 24, number 11, pages 1054-6. 9$

6. Radeff B, Kuffer R, and Samson J. Recurrent aphthous ulcer in patient infected with human immunodeficiency virus: successful treatment with thalidomide. Journal of the American Academy of Dermatology. September 1990; volume 23, number 3, part 1, pages 523-5.

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