Comprehensive, up-to-date information on HIV/AIDS treatment, prevention, and policy from the University of California San Francisco

Prospective series have implicated a wide variety of protozoal, viral, and bacterial organisms as diarrheal pathogens (Table 1). Some pathogens, like Mycobacterium avium-complex (MAC), are unique to HIV disease. Others, like Cryptosporidium, cause self-limited diarrheal illness in healthy hosts but chronic diarrhea in immunosuppressed patients.(6) The degree of immunodeficiency as expressed by the CD4 cell count is an important determinant of enteric pathogens. MAC and CMV infections are not observed in patients with CD4 cell count > 100/mm³.(7,8)

In earlier studies, pathogens were identified in over half of patients with advanced HIV disease and diarrhea.(9,10) Two large series have since demonstrated a changing clinical spectrum of diarrhea, with pathogen-negative diarrhea now representing the majority of patients.(11,12) In all series, simultaneous infections were common, emphasizing the need to exclude all pathogens thoroughly when evaluating diarrheal symptoms. Two studies have reported a dramatic decrease in cryptosporidial diarrhea over the past 5 years.(13,14)

In patients with "early" HIV disease, medications are a common cause of diarrhea, especially protease inhibitors, including Nelfinavir and Saquinavir. The diarrhea is often self-limited, lasting less than 2 to 4 weeks from initiation of medication use. Chronic/uncontrollable diarrhea, however, does occur in spite of improved CD4 cell count and decreased viral load. Other etiologies of diarrhea include idiopathic colitis, enteropathogenic Escherichia coli, and small bowel bacterial overgrowth.(15)

Small bowel bacterial overgrowth results in a clinical syndrome consisting of diarrhea and malabsorption of fat, vitamin B12, and carbohydrates. The morphologic changes reported in patients with small bowel overgrowth include villous atrophy and inflammatory infiltrates (similar to the findings in "HIV enteropathy"). Intestinal disturbances common in patients with HIV, including gastric hypoacidity, impaired intestinal immunity, or impaired intestinal motility are known to predispose to bacterial overgrowth.(16-18) In a pilot study, the prevalence of small bowel bacterial overgrowth (SBBO) in 16 patients with HIV-associated diarrhea was 38%; only one instance of SBBO was found among the control subjects.(15) Whether broad-spectrum antibiotic treatment improves symptoms and for how long treatment should continue has not been studied.

Reported evidence suggests that HIV itself may be an indirect diarrheal pathogen because viral proteins have been found in the gut. HIV has been identified in histologic specimens from the GI tract tissue in up to 40% of patients.(19-21) The virus is confined to lamina propria macrophages and enterochromaffin cells and has not found in epithelial cells. Intestinal HIV infection may also affect local humoral immunity(22) and cause motility disturbances via effects on autonomic nerves.(23,24)

An "idiopathic AIDS enteropathy" has been proposed to account for the diarrhea in HIV-infected patients who lack an identifiable pathogen. This syndrome may result from indirect effects of HIV on enteric homeostasis. Although the precise features of the syndrome are not agreed on,(25) the term implies a chronic diarrheal illness with no identified etiology in patients with advanced HIV disease.(25) Some advocate the inclusion of mucosal hypoproliferation as a defining feature.(19,25-27) Enteric HIV infection may lead to mucosal atrophy, which in turn impairs small-bowel absorption, causing diarrhea and weight loss.(28,29)

Before undertaking an extensive evaluation of diarrhea, clinicians should obtain a careful history to exclude medications, lactose or food/fatty food intolerance, inadvertent use of cathartics (e.g., megadoses of vitamin C, lactose-containing medications, sorbitol-containing foods), and symptoms suggestive of a systemic infection or neoplasm. Unfortunately, the clinical history alone is not likely to establish a specific diagnosis when due to infection. A careful history can aid in localizing the segment of luminal GI tract most severely involved. For example, symptoms of cramps, bloating, and nausea suggest gastric or small-bowel involvement, or both, raising the possibility of infection with Cryptosporidium, Microsporidium, Isospora belli, or Giardia organisms. Hematochezia and tenesmus imply large-bowel inflammation resulting from CMV, Shigella, Campylobacter, or Clostridium difficile infections. Tenesmus can occur as a result of herpes, Shigella, or Campylobacter infections. The character, frequency, color, and odor of the stool are relatively nonspecific in HIV-related GI syndromes and are therefore of little value in identifying specific infections. A history that includes multiple sexual contacts or receptive anal sex increases the possibility of sexually transmitted diarrheal pathogens.(30,31) The physical examination also provides few diagnostic clues in the evaluation of HIV-related diarrhea. Lymphadenopathy, hepatosplenomegaly, and abdominal tenderness have little diagnostic value.

The most important goal in evaluating diarrhea in patients with HIV disease is to identify treatable infections or neoplasms with the minimum work-up necessary. Once dietary causes and medications are excluded, the initial evaluation should include stool culture for enteric bacteria, a specimen for Clostridium difficile toxin (in the setting of antibiotic use), and at least three stool specimens for ova and parasite examination (including acid-fast bacilli and trichrome stain). The importance of obtaining multiple specimens was re-affirmed in a recent study of 30 patients with a confirmed diagnosis of cryptosporidiosis.(32) Only 53% of individual stool samples were positive, whereas 22 of 30 patients had at least one positive of three or more stool specimens tested.

If a diagnosis is not reached following careful stool analysis, sigmoidoscopy is appropriate to identify CMV infection. Biopsies should be obtained from abnormal regions or randomly from rectal mucosa if no abnormalities are apparent. Although colonoscopy has been advocated instead of sigmoidoscopy for diagnosis of isolated right colonic CMV,(33) this approach is not likely to be as cost-effective as reserving the colonoscopy for patients in whom sigmoidoscopy is nondiagnostic. If sigmoidoscopic evaluation is negative, upper endoscopy or colonoscopy with intubation and biopsy of the terminal ileum may occasionally uncover small-bowel infection by Cryptosporidium, Microsporidium, or M. avium.(12,32) A small-bowel biopsy should be obtained in any HIV-infected patient undergoing upper endoscopy for evaluation of diarrhea; this method has largely supplanted small-bowel capsule biopsies. Duodenal fluid can also be aspirated during endoscopy and examined for protozoal infection or small-bowel overgrowth. Compared with endoscopic procedures, the diagnostic value of radiographic contrast studies in evaluating diarrhea is very low and therefore these studies are not indicated.

When evaluation of diarrhea reveals an enteric pathogen, specific therapy should be administered if available (Table 2). Chronic administration of alternating antibiotics may be necessary for recurrent Salmonella, Shigella, Campylobacter, or Isospora infections.(34,35) An empiric trial of oral antibiotics or antiparasite therapy for the possibility of small bowel overgrowth, undetected Campylobacter, Isospora enteritis, or undetected protozoa can be considered. Sulfonamides, ciprofloxacin, tetracyclines, or metronidazole may be appropriate in this setting.

HIV-infected patients with chronic diarrhea should be treated symptomatically. Antidiarrheals, including Imodium, Lomotil, or tincture of opium drops, are often required and should be titrated individually. Lactose-containing foods should be avoided as a diagnostic and therapeutic trial. Bulk-forming agents, including effersyllium, bran, and pectin may be helpful. Nutritional repletion will increase the patient's sense of well-being, although a survival benefit has not been demonstrated. In cases of severe diarrhea, short- or long-term intravenous fluid repletion may be indicated.

Numerous agents have been tested in patients with HIV-associated diarrhea, and controlled studies have failed to define a definitive treatment for cryptosporidiosis, microsporidiosis or pathogen-negative diarrhea. Promising new data indicate that microsporidiosis and cryptosporidiosis infection may be cleared in patients receiving highly effective antiretroviral therapy.(36) The changing clinical diagnosis witnessed in the era of antiretroviral therapy has limited research on anti-infective agents. One recent study of the effects of an extract from a tropical plant showed promising declines in stool weight over 4 days of treatment in patients with AIDS and virtually no pathogens.(37)

The somatostatin analogue octreotide (administered subcutaneously) appears to be particularly effective in patients with diarrhea who lack a specific infection.(38-42) This agent's putative mechanism of action is via inhibition of a broad array of GI hormones that regulate intestinal fluid and electrolyte secretion.(43) As a result of its inhibition of cholecystokinin, gallbladder ileus with stone formation(44) and increased fat malabsorption may occur.(39)

All patients infected with HIV should have a regular nutritional and functional assessment. Weight loss, body composition changes, and exercise/functional limitations are indicators of advancing disease that may be reversible. All patients who have lost weight should have a thorough evaluation for symptoms contributing to inadequate intake and interventions to promote weight gain should be initiated promptly.

The clinical assessment should identify markers and predictors of malnutrition. A careful review of symptoms will identify barriers to adequate oral intake: anorexia, early satiety, dysgeusia, nausea, vomiting, weakness/fatigue, odynophagia, dysphagia, poor dentition, diarrhea, and abdominal pain. In addition, conditions that increase energy requirements should also be noted, including: fever, tachypnea, systemic infections, increased physical activity.

A detailed review of medications and "alternative therapies" (including herbal therapy and megadosing of vitamins and minerals) may provide insight into potential side-effects. A social history is also important to identify environmental or financial obstacles to obtaining, storing, and preparing food.

The goal of nutrition therapy is to preserve lean body mass.(55) Routine evaluations by a registered dietitian who can monitor changes in weight, body composition (body cell mass), caloric intake, and activity levels are extremely useful to prevent weight loss and malnutrition. Based on the evaluation of the patient, estimated caloric intake should be determined and 3-day food records should be administered to review patients actual intake. While guidelines for carbohydrate and fat have not been established, protein requirements should be at least 1.0 to 1.2 g/kg in the absence of secondary infection.(56) Nutrient intake should be at least 100% of the Recommended Dietary Allowance; a multivitamin is commonly suggested for patients with HIV to ensure these requirements are met.

Appetite stimulants are often effective in treating anorexia, a major cause of involuntary weight loss. Dronabinol (Marinol), a synthetic derivative of marijuana, and Megastrol acetate (Megace), a synthetic progestational drug, have been associated with increased appetite and weight.(57,58) In addition to its effects as an appetite stimulant, Marinol may also improve mood and decrease nausea.(58)

Diarrhea associated with malabsorption requires careful nutrition management. A balance must be found between controlling symptoms with a low-fat diet and maintaining caloric intake with fat-containing foods that offer caloric density. Patients with diarrhea unable to meet caloric requirements may benefit from a liquid nutrition supplement containing medium-chain triglycerides. Dietary or supplemental soluble fiber may help bind water and improve diarrhea.

If nonvolitional weight loss cannot be reduced or reversed by oral intake and oral liquid nutritional supplements, enteral alimentation should be initiated. Unless otherwise indicated, the gastrointestinal tract should be used for nutrient absorption. Kotler et al. found that patients fed by endoscopically placed gastrostomy were able to replete body cell mass, but only if the underlying illness is treated concurrently.(59) Percutaneous endoscopic gastrostomy (PEG) feeding tubes are also effective in settings of severe weight loss.(60,61)

Parenteral nutrition should be reserved for severe intestinal dysfunction, such as large volume secretory diarrhea. A clinical trial that randomized participants to total parenteral nutrition (TPN) or nutrition counseling resulted in increased weight and body cell mass in patients who received TPN, however, rehospitalization and survival were the same in both groups.(62)

Dysphagia, odynophagia, or both, due to esophagitis are very common among patients with advanced HIV disease. Both were recognized as prominent symptoms in early reports of HIV disease.(63) Their exact frequency is unknown, and not all patients with esophagitis are symptomatic.(64) The majority of patients with dysphagia or odynophagia have candidal esophagitis alone or in association with other infectious pathogens,(65-67) including cytomegalovirus (CMV), herpes simplex virus (HSV), idiopathic (nonspecific) ulceration, and Mycobacterium avium-intracellulare. Malignancies, such as KS and lymphoma, and non-HIV-related disorders, such as acid-reflux esophagitis, can also occur. Heartburn and regurgitation are usually indicative of esophageal reflux disease.

As with infections in other parts of the intestinal tract, the CD4 count can be used to direct the evaluation. Candida and HSV esophagitis are predominantly identified in patients with CD4 cell count less than 200 cells/mm³. CMV and idiopathic ulcers are noted almost exclusively below a CD4 cell count of 100 cells/mm³.

There is no way to identify the specific cause of odynophagia in the HIV-infected patient based on symptoms or physical examination alone. Like other GI symptoms, odynophagia in the presence of multiple co-infecting organisms makes it impossible to ascribe a symptom or sign to a single pathogen. Barium swallow (double-contrast) findings may be suggestive of infection or neoplasm but not diagnostic. Endoscopy with biopsy is the best method of establishing a specific etiology for dysphagia or odynophagia. During the endoscopy, careful examination of the entire mucosa must be undertaken. If a confluent candidal exudate is noted, removing the exudate to examine the underlying mucosa for concomitant pathology should be considered. Patients with esophageal ulcers should have more than six biopsy specimens obtained from the ulcer(s). In a study of 100 patients with esophageal ulcers, Wilcox et al. reported that the first three biopsy samples yielded a CMV diagnosis in 80% (40 of 50 patients with CMV).(68) In 5 patients (10%) with CMV and 3 of 4 patients with concomitant HSV and CMV, 7 to 10 biopsies were needed to make the diagnosis.

In general, cultures of esophageal biopsy specimens for fungi and viruses are less useful than biopsies, because cultures alone do not distinguish between true pathogens and colonizing organisms.

An empiric approach to managing esophageal symptoms is the most reasonable approach in the patient with AIDS. Given the preponderance of candidal infection, patients with odynophagia who have oral thrush should be treated empirically with fluconazole (100 to 200 mg/day) or itraconazole (200 mg/day) given their superior efficacy compared to ketoconazole (200 mg/day). Esophageal symptoms due to Candida will sometimes improve with treatment even though endoscopic evidence of infection persists.(69) Furthermore, symptomatic improvement of esophageal symptoms is probably the most important goal, because it leads to increased oral intake and better nutritional status.

Refractory Candida esophagitis requires treatment with amphotericin B. Herpes esophagitis responds to acyclovir (200-mg capsules every 4 hours). Rare instances of acyclovir-resistant herpes have been reported in patients with advanced HIV disease.(70) Such patients may respond to foscarnet.(71) Documented infections with CMV generally respond to a 2- to 3-week course of ganciclovir. Relapses may require an additional course of therapy, a maintenance regimen, or both.(72,73) The efficacy of foscarnet is comparable to that of ganciclovir,(73) with possible adverse effects including nephrotoxicity and hypocalcemia.(74)

Nonspecific ulcerations may be treated with a short course of oral corticosteroids (40 mg/day, tapered over 3 weeks)(75,76) or thalidomide (200 mg/day),(77,78) or with combinations of H-2 antagonists and sucralfate.(79) The basis for the response of these lesions to corticosteroids is unknown; infectious causes should be assiduously excluded before administering steroids in this setting.

Abdominal pain is common in patients with HIV infection, and it may portend a catastrophic complication. No data exist on the exact frequency of this symptom.(80,81) When generating a differential diagnosis for an HIV-infected patient with abdominal pain, the clinician must consider not only the manifestations of opportunistic infections and neoplasms but also the more common causes of abdominal pain that occur in otherwise healthy persons. Several published studies specifically address the diagnosis of abdominal pain in HIV disease and underscore the broad spectrum of potential causes.(82-86)

The differential diagnosis for abdominal pain in HIV-infected patients presented in (Table 4) is organized by the pain's site of origin. For each organ system, a list of potential complications and their likely causes is noted. This information is based primarily on case reports, which are noted in the table. The table excludes non-HIV-related diagnoses, which are more common causes of abdominal pain even in patients with HIV disease. Overall, cytomegalovirus (CMV) infection of the bowel and biliary tract are the most common HIV-associated causes of abdominal pain.

The patient's history is important in identifying the origin of abdominal pain. In general, the associated symptoms and signs should help identify the particular organ involved. The specific work-up is similar to that for a patient without HIV infection. An exception is that abdominal sonography and computed tomography scanning are useful early in the assessment of abdominal pain in HIV-infected patients and may highlight regions of disease not usually suspected clinically.(87) Unsuspected findings have often included thickening of the gallbladder or colonic wall, focal hepatic lesions, biliary ductal dilatation, pancreatic infiltration, adenopathy, and peritoneal thickening. Abnormal bowel wall thickening in patients with HIV infection should be pursued with endoscopic biopsies. Rockey et al. reported a specific diagnosis in 7 of 15 patients (64%), including CMV, lymphoma, and MAC.(88)

The quality and duration of the abdominal pain may implicate specific diseases. In general, perforation results most often from CMV infection and occurs frequently in the distal small bowel or colon. Lymphoma or KS may also perforate, either spontaneously if the tumor is bulky or due to tumor lysis following chemotherapy or radiation. Obstruction is most likely to develop from an intestinal neoplasm but may also develop from an inflammatory mass or stricture. Intussusception may be an unusual form of lymphomatous obstruction. Infectious enteritis may lead to dull, intermittent abdominal pain in the absence of obstruction or perforation. This is particularly true of infection by Cryptosporidium and Mycobacterium avium-intracellulare complex (MAC) but may also occur in infections from other protozoa, as well as from enteric bacteria including Salmonella, Shigella, and Campylobacter.

Infectious or nonspecific peritonitis in the absence of bowel perforation is increasingly recognized. Infectious etiologies may include histoplasmosis,(89) tuberculosis,(82) MAC, Vibrio vulnificus,(90) toxoplasmosis,(91) and Cryptococcus,(92) in addition to lymphoma.(93) High-protein ascites of uncertain etiology has also been reported and may necessitate laparoscopy to identify a cause.(92)

Pancreatitis can cause abdominal pain in patients with advanced HIV disease and may arise for a variety of reasons. Affected patients usually have elevations of amylase and lipase, unless acute inflammation occurs in a patient with pre-existing underlying chronic pancreatitis. Amylase elevations in the absence of pancreatic disease may indicate macroamylasemia, which occurs in patients with and without HIV disease.(94) Medications are the most common cause of pancreatitis in HIV, particularly pentamidine,(95,96,97) dideoxyinosine (ddI),(98,99) and trimethoprim-sulfamethoxazole.(100) Pentamidine-induced pancreatitis may develop following either inhaled(96) or parenteral administration,(97) and it is associated with the typical clinical features of pancreatitis.(95) The clinical course may be mild, severe, or fatal; it is often accompanied by dysregulation of glucose metabolism.(101,102,95)

Potential infectious causes of pancreatitis in HIV disease are multiple. Most common is CMV,(103) followed by M. tuberculosis,(104) M. avium,(105) Cryptococcus,(106) and herpes simplex (HSV).(107) Infectious pancreatitis may not always be clinically obvious; it should be suspected in any patient with abdominal pain and elevated amylase.(103) In CMV-induced pancreatitis, inclusions may be demonstrable either in ductal epithelium or acinar cells. Fine-needle aspiration may be able to uncover these findings antemortem in patients in whom this infection is suspected. Pancreatic infiltration by lymphoma(108) and KS(109) occurs occasionally, manifested either by mass effect on adjacent duodenum or exocrine insufficiency if the pancreatic duct is obstructed.

Table 5 defines abdominal pain in terms of the four most common pain syndromes, likely causes, and diagnostic methods. The duration and severity of symptoms dictate the urgency of evaluation. For example, patients with dull, insidious abdominal pain can be evaluated with less urgency than patients who develop acute, severe abdominal pain with evidence of peritonitis.

Managing abdominal pain begins with deciding if the patient requires surgery.(101) In general, the indications for surgical intervention in HIV-infected patients are similar to those in patients without HIV infection. Intestinal perforation or obstruction almost always requires surgical management, despite the increased perioperative and postoperative risk for patients with advanced HIV disease. Clinicians must submit all tissue specimens for viral and fungal culture and for pathologic examination, and mesenteric nodes should be biopsied.(110) Laparoscopic surgery may provide a less invasive alternative in select patients, such as those with cholecystitis. The main goal of any surgical procedure should be the palliation of symptoms. Prolonged anesthesia and extensive tissue resection should be avoided if possible.

The morbidity and mortality in early reports of surgical procedures in patients with advanced HIV disease have been exceedingly high.(83,86) This is due partly to the underlying poor health of patients with advanced HIV disease who require laparotomy; most have CMV infection, which tends to occur in late-stage HIV disease. Complications and mortality are far less likely in patients with asymptomatic HIV infection,(111) although the exact frequency relative to comparable non-HIV-infected persons has not been reported.(83) The result of clinical evaluation determines the nonsurgical management of abdominal pain. Any treatable infection contributing to the symptoms should be managed appropriately. Symptoms due to lymphoma or KS may respond to chemotherapy or radiation therapy. Symptomatic treatment with analgesics may be indicated in addition to specific antibiotic or antineoplastic regimens. HIV-related conditions and chronic opportunistic infections may improve with HAART.

Anorectal problems may occur in any HIV-infected patient, but they are particularly common among homosexual men. A broad array of anorectal problems are prevalent in the healthy homosexual male population, in part because of the prevalence of anal intercourse and anilingus.(101,112) Anal warts and fissures, infections with lymphogranuloma venereum, gonorrhea, syphilis, and herpes viruses are well-recognized pathogens, although they do not necessarily imply immunodeficiency in their hosts (Table 6). They have been the subject of numerous reports antedating the HIV epidemic.(31,113,114)

The frequency of anorectal disease among homosexual male patients with advanced HIV disease is quite high. In a large New York City series of 340 such patients, the incidence of anorectal disease was 34%.(115) Perirectal abscesses, anal fistulae, and infectious proctitis were the most common findings, but lymphoma, ulcerations due to tuberculosis, and histoplasmosis were also present. Idiopathic ulcerations in this region similar to those seen in the esophagus in HIV disease occur with increased frequency.(116)

Anorectal carcinomas are more common in homosexual men than in other members of the population.(117-121) These neoplasms appear to result from chronic perianal herpes or papillomavirus infections acquired through sexual contact.(122) HIV-infected subgroups other than homosexual men do not appear to have an increased incidence of anorectal carcinoma.

In HIV-infected patients, physical examination should include careful inspection of the skin and mucous membranes as well as palpation of the lymph nodes. Careful visual inspection of the anus for fissures and masses should precede digital examination. Palpation of the anal canal may reveal masses or fissures not otherwise evident. All patients with anorectal symptoms should have anoscopy and sigmoidoscopy (rigid or flexible) with mucosal biopsy, even if the mucosa appears unremarkable by gross examination.

The stage of HIV disease largely determines healing of anorectal disease following surgical or nonsurgical therapy. Surgery is most likely to succeed in patients in the earlier versus later stages of HIV infection,(111,123,124) although the healing rates may still be slower than in immunocompetent patients. In patients with idiopathic ulcerations, debridement and use of either systemic or intralesional corticosteroids has been successful. In chronically ill patients, a more conservative approach to surgical management seems warranted depending on the extent of debility. All efforts should be directed toward identifying infections and providing symptomatic relief, reserving more aggressive measure for those in whom less invasive efforts fail.

Although gastrointestinal (GI) bleeding occurs in less than 1% of patients with HIV disease, it may pose difficult diagnostic and therapeutic challenges. Moreover, GI bleeding is independently associated with reduced survival.(125) GI bleeding in patients with HIV disease is as likely to arise from lesions not unique to HIV infection as from HIV-associated opportunistic infections or neoplasms.(125-127) Common lesions not unique to HIV infection include peptic or stress-related ulcer disease, variceal hemorrhage due to portal hypertension, inflammatory bowel disease, diverticular disease and colonic polyps, and neoplasia. None of these diseases occurs more commonly in HIV-infected patients than in healthy persons. This review addresses only those infectious processes and neoplasms associated exclusively with HIV infection that may on rare occasion cause GI bleeding.

Cytomegalovirus (CMV) involvement of the GI tract may cause bleeding by inducing vasculitis in affected tissue. The vasculitis results in ischemia, infarction, or both and occurs most commonly in the colon or distal small bowel.(128,129) A similar mechanism probably accounts for the bleeding associated with CMV infection of the esophagus and stomach.(130) Hemorrhage from colonic or esophageal infection may be due to either focal or diffuse inflammation.(129,130) Occasionally, patients can develop a pancolitis that is clinically similar to the colitis seen in patients with inflammatory bowel disease or mesenteric ischemia.(129) Candida albicans may sometimes induce esophageal hemorrhage via direct fungal invasion, causing a severe erosive esophagitis.(131)

Herpes esophagitis has only rarely caused esophageal hemorrhage in non-HIV-infected patients.(132) In HIV-infected patients, however, the later stages of herpes infection of the esophagus are associated with mucosal ulcerations that may coalesce into a diffuse hemorrhagic esophagitis.

Cryptosporidiosis occasionally causes enteritis associated with hematochezia,(133) although the majority of patients with cryptosporidiosis have severe diarrhea with little or no hemorrhage.(134)

Enteritis associated with Salmonella, Shigella, or Campylobacter occurs with increased frequency in HIV-infected patients, as compared with non-HIV-infected patients.(135) These infections are associated with watery diarrhea that may be grossly or microscopically bloody.

Several other enteric infections associated with hemorrhage occur with increased frequency in sexually active homosexual men, regardless of whether they are infected with HIV. These organisms include Entamoeba histolytica and chlamydia.(31) The clinical features of such infections in patients with HIV disease are similar to those seen in otherwise healthy homosexual men. Rarely, histoplasmosis leads to colonic ulcerations that bleed.

Neoplasms associated with HIV disease may cause intestinal bleeding. In a small series from San Francisco, KS was the most common lesion found in patients with HIV-related GI bleeding.(127) Reports describe isolated cases in which ulcerated GI KS lesions bled spontaneously.(85,127,136) In general, however, KS lesions are asymptomatic. In a series of 20 patients with intestinal KS and HIV disease from San Francisco General Hospital, no episodes of GI bleeding occurred either spontaneously or after endoscopic biopsy.(136)

Primary intestinal lymphoma occurs more often in HIV-infected patients than in non-HIV-infected patients.(137) Bleeding from these tumors may occur.

Gastrointestinal bleeding in a patient with HIV infection should be evaluated with the same approach used in assessing a non-HIV-infected patient. The utility of endoscopy and the patient's prognosis depend on the number and severity of concomitant diseases.(126) First, one should determine how brisk the bleeding is and whether it arises from an upper- or lower-tract lesion. Upper endoscopy is usually necessary to define the source of any severe upper-tract bleeding. To evaluate acute lower-tract hemorrhage, a nuclear red blood cell scan to define the approximate site of bleeding is more useful than immediate colonoscopy. Endoscopic mucosal biopsy of briskly bleeding lesions is generally not appropriate because of the risk of precipitating more severe hemorrhage. After the bleeding subsides, a repeat of the examination with mucosal biopsy can be performed. Barium contrast studies in evaluating GI bleeding are of limited value.

Appropriate management of severe GI bleeding due to HIV-related diseases does not require a specific diagnosis. Treatment consists of blood-product support and, if necessary, surgery. Hemostasis should be achieved by nonsurgical endoscopic means wherever possible, including direct injection of bleeding lesions with sclerosant or epinephrine or use of heater-probe cautery or electrocautery. Intermittent blood-product replacement may be necessary in patients with chronic, idiopathic blood loss to prevent severely symptomatic anemia. Surgery should be avoided if possible but should be undertaken if noninvasive means fail.

Most patients will experience hepatobiliary manifestations at some point during the course of their HIV disease, with hepatomegaly and/or jaundice in 50% and abnormal liver function tests in over 80%. Despite their frequency, however, the approach to patients with such abnormalities remains problematic. Although most conditions found on liver biopsy represent systemic opportunistic infections or neoplasms, liver disease itself is rarely the cause of death.(157) Instead, the clinical and histologic expression of most diseases in the liver is attenuated because of the impaired immune response. In addition, most liver disorders that are diagnosed in patients with AIDS reflect advanced immunosuppression and occur late in the natural history of AIDS, when little can be done to improve overall outcome.

HIV can involve the liver directly, as demonstrated by the presence of HIV p24 within Kupffer cells and hepatic endothelial cells(158) and HIV messenger RNA within hepatocytes.(159) Hepatic macrophages and endothelial cells express the CD4 surface molecule and have been shown to support viral replication in vitro.(160) It remains unclear, however, whether HIV itself directly damages the liver. The quantity of HIV antigens in immunohistochemical studies does not correlate with the degree of histologic abnormalities, and normal histology can be seen.(161)

Mycobacterium avium complex (MAC) is the most common opportunistic pathogen found when liver biopsy is performed in patients with HIV disease, accounting for 38% of diagnoses in one series.(162) Infection with MAC occurs late in the natural history of AIDS, with CD4 counts generally less than 50 x 10⁶ cells/ml. Because hepatic involvement occurs in the setting of disseminated disease, systemic symptoms dominate the clinical picture,(163) although a prominent elevation of serum alkaline phosphatase is common.(164) Treatment with multiple antibiotics generally produces an initial response; however, because of the advanced immunosuppression in these patients, the long-term outcome remains poor.

Hepatic involvement with MAC must be distinguished from infection with Mycobacterium tuberculosis. Extrapulmonary tuberculosis occurs in over 50% of infected patients with AIDS.(163) Infection occurs at a less advanced stage of immunocompromise than MAC, which may account for differences seen histopathologically, including well-formed granulomas and caseation. Tuberculosis cannot be distinguished from MAC by clinical features or histopathology alone; therefore, culture is required for positive diagnosis. In addition, determination of antimicrobial sensitivities is necessary to guide appropriate therapy. Unless a multidrug-resistant strain is present, response to treatment is good, with a median survival of 16 months.(165)

Peliosis hepatis has been recognized as a bacterial syndrome in patients with AIDS, following the discovery of its causative agent, Bartonella hensalae. Early in the AIDS epidemic, a syndrome consisting of dilated, blood-filled hepatic sinusoids and elevated liver function tests was recognized in conjunction with cutaneous bacillary angiomatosis.(166) Histopathologic studies revealed clumpy granular, purple material within both hepatic and cutaneous lesions, which proved to be bacteria by electron microscopic analysis. Further investigations employing polymerase chain reaction tests (PCR) identified the organism as a gram-negative bacillus closely related to Bartonella quintana, the causative agent of trench fever. In a recent case-control study, infection with B. Henselae has been epidemiologically linked to exposure to cats.(167) Histologically, peliosis consists of numerous blood-filled cystic spaces within the hepatic parenchyma without an endothelial lining. Serum transaminase levels are modestly elevated, with more prominent elevations of serum alkaline phosphatase. In addition to cutaneous lesions, patients can experience fevers, sweats, rigors, right upper quadrant pain, or pain from bony lytic lesions. Successful treatment regimens have included erythromycin, doxycycline, ciprofloxacin, and antituberculous regimens, although prolonged therapy for several months may be required.

Fungi usually involve the liver only with disseminated disease. These infections share a nonspecific clinical presentation, including unexplained fever, hepatomegaly, and elevated alkaline phosphatase levels, although large fungal abscesses are occasionally seen on imaging studies. Hepatic involvement can accompany cryptococcal meningitis in the setting of hematogenous dissemination. Opportunistic infections with Histoplasma, Coccidioides, Candida, and Sporothrix organisms occur less commonly. Although a nonspecific attenuated granulomatous reaction is characteristic, liver biopsy is generally not required fro diagnosis.(168) Response to prolonged antifungal therapy is variable, with death resulting from disseminated infection rather than from hepatic involvement itself.

Pneumocystis carinii is the most common protozoal pathogen among patients with AIDS, and liver involvement occurs in 38% of patients.(169) Pulmonary symptoms dominate the clinical presentation, although a few cases of primary hepatic involvement have been reported.(163) On liver biopsy, a foamy eosinophilic exudate is characteristic, with the organism demonstrable on silver stain.(170) Response to treatment with parenteral pentamidine or trimethoprim-sulfamethoxazole has been reported, although no controlled trials have been conducted.

Kaposi's sarcoma is seen almost exclusively in homosexual men with AIDS, as opposed to other risk groups. Disseminated disease is common, with hepatic involvement in one-third of patients at autopsy.(171) Although serum alkaline phosphatase may be elevated, visceral disease is often asymptomatic, even with extensive involvement. Histologically, the lesions are easily identified as solid dark red to purple nodules in the portal regions, filled with densely packed spindle-shaped endothelial cells that form slitlike vascular channels.(172) Although lesions may respond to radiotherapy or chemotherapy, hepatic disease is not treated unless symptomatic, because the nodules themselves rarely are a direct cause of death or severe morbidity.

Extranodal presentation of non-Hodgkin's lymphoma is common in patients with advanced AIDS, with liver disease typically in the setting of multiorgan involvement.(172) Infection with Epstein-Barr virus (EBV) has been implicated with the finding of EBV genomic fragments within tumor cells by DNA hybridization as well as the universal presence of anti-EBV antibodies in patients with NHL.(136) Serum alkaline phosphatase elevations are most sensitive for hepatic involvement, with elevated transaminases and bilirubin in advanced disease. Although approximately 50% of patients have been reported to respond to various chemotherapeutic regimens, disease-free intervals have been short and recurrence rates high.(173) Overall survival, however, is no worse than in AIDS patients without lymphoma, most likely because NHL usually accompanies advanced immunocompromise.

That coinfection with HBV and HIV is common is not surprising given their similar modes of acquisition. The prevalence of seropositivity for past or present infection with HBV approaches 90% in HIV-infected homosexuals.(174) Similarly high rates of coinfection have been seen in injection drug users.(175) The prevalence of HBV seropositivity among HIV-infected patients, however, is no higher than that seen in control patients without HIV, suggesting that coinfection likely reflects lifestyle practices that predispose to both infections.(176)

In patients with past or present HBV infection, HIV infection leads to alterations in HBV serology and viral replication. Following acute HBV infection, the virus is cleared in 95% of immunocompetent patients. In contrast, 50% of HIV-coinfected patients will develop chronic infection.(177) Several reports have described reappearance of Hb_sAg in HIV-infected patients previously thought to be immune to HBV, as indicated by the presence of anti-Hb_s.(178,179) In addition, there is an accelerated loss of naturally acquired anti-HB_s even in patients who remain HB_sAg negative.(180,181) Associated with this reduction in immunity to HBV is increased prevalence of HB_eAg expression, elevated mean levels of DNA polymerase, and increased titers of anti HB_c.(177,178,182,183) Thus, more patients with HIV and HBV coinfection are in the chronic HBV carrier state, with highly infectious serum and body fluids, as compared with those who are not infected with HIV.(184)

The impact of HIV on the severity of chronic HBV infection is less clear. Several case series have suggested that HIV-coinfected patients have milder clinical disease, with reduced severity on histologic examination and less pronounced elevations of serum aspartate aminotransferase (AST) and alanine aminotransferase.(177,182,185) Corroborating these results, Scharschmidt et al. found no difference in survival up to 48 months between 35 patients with HIV/HBV coinfection and 70 patients infected with HIV alone, regardless of whether progression to overt acquired immunodeficiency syndrome (AIDS) occurred.(182) In a similar study, however, Housset et al. obtained contradictory results, with significantly shorter survival among HIV/HBV coinfected patients compared with those infected with HIV alone. Furthermore, liver disease was the most common cause of death among these patients.(185)

Vaccination against HBV has been recommended for all patients infected with HIV. Unfortunately, HIV infection reduces the efficacy of vaccination in these patients. Several studies have demonstrated suboptimal response to plasma-derived vaccine in both magnitude and duration of the antibody response.(186-188) Lack of responsiveness does not clearly correlate with CD4 count. Among those patients who do respond, loss of protective anti-HB_s is seen in 43% at 4 years, compared to 8% of immunocompetent controls.(181)

Historically, there has been little enthusiasm or rationale to treat HBV infection in HIV-coinfected individuals since the latter disease rather than the former had been the major determinant of life expectancy for most patients. This situation is changing rapidly, however, as therapies for HIV improve and patients live longer, developing greater risk for decompensated liver disease. Unfortunately, treatment options remain limited. Interferon-alpha is the only drug currently approved for treatment of chronic HBV. In immunocompetent patients, a standard course of treatment leads to loss of HB_eAg and HBV-DNA in 35%, but if such a response can be induced, it is generally maintained long-term. HIV-coinfected patients, however, have been identified in a meta-analysis as a subgroup with poor response to interferon.(189) This has been confirmed in a small controlled trial, in which an 8% response was seen in HIV-positive subjects, compared with 39% in controls.(190) Newer antiviral drugs such as lamivudine, which directly inhibit HBV replication rather than modulating the immune response, may hold more promise for effective treatment of these patients in the future.

Hepatitis C (HCV) shares a parenteral mode of transmission with HIV and is seen more commonly among intravenous drug users than in other risk groups. The reported prevalence of HIV and HCV coinfection(191-193) has ranged between 7% in a university clinic setting and 89% among intravenous drug users. Such estimates are imperfect, however. Most studies have utilized first-generation HCV antibody assays; in addition, seroreversion with loss of anti-HCV antibody has been reported in up to 20% of patients.(194) In this population, the detection of HCV RNA by hybridization assays or by polymerase chain reaction is the gold standard for diagnosis.

In the presence of an intact immune system, HCV is an indolent disease, with progression to liver failure in a minority of patients over a time span measured in decades. This natural history appears to be accelerated in immunocompromised patients. Similar to HBV, viral replication as measured by HCV-RNA level is greater in patients with HIV coinfection, and a higher prevalence of liver failure has been seen in HIV-coinfected hemophiliacs compared to those with HCV infection alone.(195,196) Furthermore, the risk of clinical liver disease increases with progression of AIDS as measured by p24 antigenemia and decreased CD4 counts. In a cross-sectional study of 512 HIV-infected patients, however, Wright et al. found no difference in overall mortality between those with and without HCV.(197) This result suggests that, as with HBV, it is the infection with HIV rather than viral hepatitis that ultimately determines the outcome in these patients.

Currently, interferon-alpha is the only drug approved by the FDA for treatment of HCV. Even among immunocompetent patients, the long-term benefit of such therapy remains unclear. Data on the treatment of immunocompromised patients remain extremely limited. Two small uncontrolled studies have been performed to investigate interferon-alpha treatment of HCV in HIV-coinfected patients.(198,199) Although these studies showed reduction in HCV RNA levels and improvements in histology, more definitive trials are needed. Given the absence of any clearly effective regimens and the questionable impact of HCV infection on the overall prognosis of patients coinfected with HIV, aggressive treatment cannot be recommended at the present time.

Several caveats should guide the evaluation of abnormal liver function tests or hepatobiliary symptoms in patients with AIDS. First, histologic and biochemical abnormalities are ubiquitous, but liver disease itself seldom causes significant morbidity. Second, hepatic involvement by opportunistic infections and neoplasms is generally part of a disseminated process. Such diseases can usually be diagnosed at an extrahepatic site and are often poorly amenable to treatment. In contrast, biliary complications of AIDS require an aggressive approach, because they frequently are symptomatic and are potentially fatal. Moreover, effective palliation is available for most of these patients by endoscopic or surgical means.

The role of liver biopsy in patients with AIDS has been especially controversial. Several reported series have shown that histologic abnormalities are seen on almost all biopsy specimens, the majority of which are nonspecific.(170) The yield of specific, treatable diagnoses is quite low, however, and most of these diagnoses could be made by less invasive means, including blood cultures and aspirates of bone marrow or lymph nodes.(162) Because liver biopsy rarely provides unique information to influence therapy or improve survival, it cannot be recommended for routine evaluation of abnormal tests of hepatic function in patients with AIDS. Liver biopsy may be indicated in certain situations, however, when severe symptoms and marked biochemical abnormalities are present, and after less invasive investigations have proved unrevealing.

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