Humberto Sifuentes, MD, Parakkal Deepak, MD, and Eli D. Ehrenpreis, MD
What is the basic management of opportunistic infections occurring in human immunodeficiency (HIV) and acquired immune deficiency syndrome (AIDS)?
Because of highly active antiretroviral therapy (HAART), when opportunistic infections are diagnosed, both the opportunistic infection and the underlying HIV infection are treated at the same time.
Which HAART medications are associated with pill-induced esophagitis?
Zidovudine (AZT) and zalcitabine (ddC).
What is the most common opportunistic infection involving the esophagus in HIV-infected patients?
Candida is the most common fungal infection and cytomegalovirus (CMV) is the most common viral infection.
What causes oral hairy leukoplakia?
Epstein–Barr virus (EBV). Oral hairy leukoplakia appears as white plaques that coat the lateral aspects of the tongue.
What area of an ulcer would you biopsy to detect herpes simplex virus (HSV)? CMV?
Biopsy the edge (area of viral replication) of the ulcer to detect HSV and the ulcer base (CMV does not invade squamous epithelium) to detect CMV.
What name is given to an ulcer seen on endoscopy in an HIV-infected patient with histopathology showing no viral cytopathic effect and no clinical or endoscopic evidence of reflux or pill-induced ulceration?
Idiopathic esophageal ulcer. These ulcers often present with odynophagia and substernal chest pain and may be deep and multiple in number. Ninety percent respond to oral or intralesional steroids. They also appear to be responsive to thalidomide.
True/False: Empiric treatment with an antifungal agent such as fluconazole should be administered to a patient with HIV who is complaining of dysphagia without odynophagia and who has oral thrush on exam.
True. The presumptive diagnosis is esophageal Candidiasis. Up to two-thirds of patients with Candida esophagitis have oral thrush. Odynophagia is usually not severe with candidiasis and if present should prompt an endoscopic evaluation for possible mucosal ulceration.
Why is ketoconazole less effective than fluconazole in the treatment of Candidiasis?
The absorption of ketoconazole and itraconazole is pH dependent—requiring an acidic pH for absorption. Achlorhydria has been well described in association with HIV infection. Concomitant use of H2 blockers or proton pump inhibitors is also common in HIV-infected patients. Absorption of fluconazole is not pH dependent.
What is the most common gastrointestinal symptom in HIV-infected patients?
Diarrhea. Prevalence rates of 50%–90% have been recorded.
What is the most common infection of the small bowel in patients with AIDS?
Cryptosporidiosis. This protozoa causes a self-limited diarrheal illness in normal hosts. However, in patients with AIDS, this infection can cause high volume, watery diarrhea often without the presence of fecal leukocytes and usually with malabsorption and weight loss. The disease course is worse with increasing degrees of immunodeficiency. Nitazoxanide is approved by the U.S. Food and Drug Administration for the treatment of cryptosporidiosis in non-HIV infected patients but, to date, this agent has not been effective for the treatment of HIV-infected patients. The treatment of choice in HIV-infected patients with cryptosporidiosis is HAART. Paromomycin is no more effective than placebo in HIV-associated cryptosporidiosis.
What measure can patients with CD4 counts <200 take to decrease infection with Cryptosporidium?
Boil or filter the water. This eliminates oocytes. They should also minimize oral exposure of water from lakes, streams, and public swimming pools.
In HIV-infected patients, name a protozoal infection of the small bowel that responds well to antibiotic therapy.
Isospora belli. This infection is endemic in developing countries (Haiti and Africa). The treatment of choice is trimethoprim-sulfamethoxazole. Patients intolerant to sulfonamides can use pyrimethamine. Relapses can occur and require maintenance therapy.
An HIV-positive patient with chronic diarrhea undergoes small bowel biopsy. On electron microscopy, a “cat’s eye” appearance of the enterocyte nucleus with a supranuclear indentation is noted. What is the cause of the diarrhea?
The appearance of the nucleus is caused by a merozite indicating infection with microsporidium, probably the species Enterocytozoon bieneusi. This species accounts for about 80% of all microsporidial infections and is often refractory to treatment. Encephalitozoon intestinalis makes up the other 20% of microsporidial infections. Albendazole is treatment of choice for E. intestinalis. No consistent therapy exists for E. bieneusi. Although albendazole has been reported to reduce frequency and volume of diarrhea, it does not clear the organism on stool specimens or duodenal biopsy specimens.
What is the most common viral infection that causes diarrhea in AIDS?
Cytomegalovirus. The infection may be limited to the right side of the colon in up to 18%–30% of patients. Hence, patient should undergo a full colonoscopy particularly if the distal colon is endoscopically normal.
What are the serious complications of CMV enteritis and colitis?
Severe abdominal pain, mucosal ischemic ulcerations, bleeding, fistula, and perforation. Patients may present with an acute abdomen. CMV enteritis or colitis should be suspected in this clinical setting in a patient with AIDS and a very low CD4 count.
What is the initial treatment of choice for intestinal CMV infection?
Ganciclovir or valganciclovir. Although effective, cidofovir and foscarnet are considered second-line treatments because of the limited studies in GI disease and associated toxicities. Prior to treatment, the patient should undergo ophthalmologic examination to evaluate for CMV retinitis.
What is the most significant side effect of treatment with ganciclovir and valganciclovir?
Neutropenia. These drugs cause neutropenia in 20%–40% of patients and thrombocytopenia in 5% of patients. Zidovudine has potentiating effects on drug-induced neutropenia. Hence, other HAART medications are recommended.
What is the most common bacterial cause of diarrhea in HIV-infected patients?
Clostridium difficile associated diarrhea. The incidence of C. difficile in this population is increased due to the frequent use of antibiotics and increased amount of time spent hospitalized. The clinical presentation, response to therapy, and relapse rates are similar to immunocompetent patients.
How do the presentations of gastrointestinal Mycobacterium avium complex (MAC) and Mycobacterium tuberculosis (MTB) in HIV-infected patients differ?
MAC is the most common mycobacterial infection in patients with AIDS. MAC usually presents as an asymptomatic infection, most commonly in the duodenum and can appear as patchy areas of edema, erythema, friability, erosions, nodularity, a frosted appearance, or yellowish nodules or plaques on endoscopy. Alternatively, massive small intestinal infiltration with MAC may cause diarrhea and malabsorption. Concomitant hepatomegaly or splenomegaly with anemia is often present. Treatment includes 2 or 3 antimicrobials for at least 12 months. Commonly used first- line drugs include macrolides (clarithromycin or azithromycin), ethambutol, and rifamycins (rifampin, rifabutin). Aminoglycosides, such as streptomycin and amikacin, are also used as additional agents. Prophylaxis is recommended for all patients with CD4 cell count less than 50/mm3. Effective drugs include macrolides and rifabutin.
MTB usually causes symptomatic illness and generally affects the ileocecal region. MTB has been associated with the formation of bulky mesenteric or retroperitoneal adenopathy with areas of central necrosis seen on computed tomography. MTB infection responds well to multidrug antitubercular therapy.
True/False: Octreotide plays a major role in the management of chronic diarrhea in patients with AIDS.
False. Octreotide is a somatostatin analogue that acts as an antisecretory and antimotility agent. Some research suggests that HIV shares amino acid sequences with vasoactive intestinal peptide (VIP), thus upregulating the VIP receptors and contributing to chronic HIV-associated diarrhea. Octreotide has been postulated to interfere with this mechanism. Nevertheless, a randomized, placebo-controlled trial failed to show any benefit of octreotide as treatment of HIV-infected patients with chronic diarrhea.
What malabsorptive disease can mimic MAC infection of the gastrointestinal tract?
Whipple’s disease. After the atypical mycobacteria are ingested from contaminated water, they are phagocytosed by macrophages but are not killed. They invade tissues causing lymphadenopathy and organomegaly. In the gut, they invade the wall impairing lymph flow and causing fat malabsorption and exudative enteropathy. Histologically, foamy macrophages are seen in the small intestinal lamina propria. These are indistinguishable from Whipple’s disease; however, an acid fast stain will show numerous acid fast organisms in the case of MAC.
How does MAC cause peritonitis?
Liquefaction necrosis. An abdominal lymph node may necrose and result in peritonitis.
Describe a rational stepwise approach to the evaluation of chronic diarrhea in patients with AIDS.
Careful attention should be directed toward a complete history and physical examinations including the HAART medications that the patient is taking. If one of the medications is a potential offender, consider discontinuation of the drug and observe for resolution. Diagnostically, multiple stool samples should be obtained. If nondiagnostic and CD4 count is < 200 cells/mm3, consider sigmoidoscopy (or colonoscopy with biopsies of the terminal ileum) and/or upper endoscopy with small bowel biopsy and aspirate. These tests may provide a diagnosis in an additional 50% of cases.
Which of the HAART medications cause diarrhea as a side effect?
As a class, diarrhea is most commonly seen with protease inhibitors, prominent among which are nelfinavir (up to 50%), and up to 20% of those taking lopinavir/ritonavir and fosamprenavir/ritonavir. The mechanism of diarrhea is unclear. Additionally diarrhea has also been described with the nucleoside analogue reverse transcriptase inhibitor (RTI) didanosine, stavudine, and abacavir.
What is the HIV/AIDS wasting syndrome?
The involuntary loss of greater than 10% body weight from baseline over 12 months or 5% over 6 months with no identifiable infectious or neoplastic cause.
What is the most significant cause of weight loss in AIDS patients without gastrointestinal symptoms?
Decreased caloric intake. Stable weights are often punctuated by episodic short-term weight loss when patients develop opportunistic infections. Small intestinal malabsorption has been shown to commonly occur in these patients as well. In addition, altered energy expenditure and adrenal insufficiency may contribute.
All patients with HIV disease should have what vitamin level checked because of a high prevalence of deficiency?
Vitamin B12. A landmark paper on the subject found a 15% prevalence of vitamin B12 deficiency in an unselected group of patients with AIDS and 7% prevalence in asymptomatic HIV infection. In AIDS patients with chronic diarrhea, the prevalence of B12 deficiency may be as high as 39%.
What mechanisms are responsible for the development of vitamin B12 deficiency in HIV-infected patients?
The most important mechanism is ileal absorptive dysfunction. Additional factors include achlorhydria (causing decreased liberation of food-bound cobalamin), decreased intrinsic factor secretion, bacterial or parasitic overgrowth in the small bowel, and pancreatic insufficiency.
What is the most common cause of pancreatitis in patients with HIV/AIDS?
Drug-induced. Common offending agents include pentamidine (inhaled and parenteral), didanosine (ddI), zalcitabine (ddC), and occasionally trimethoprim-sulfamethoxazole. Less commonly, infections involving the pancreas with organisms such as CMV, Cryptosporidium, and MAC can also cause pancreatitis.
True/False: Pancreatic toxicity from pentamidine causes hypo- and hyperglycemia.
True. Direct toxicity to the pancreatic islet cells causes insulin release and low blood sugar levels. Hyperglycemia occurs later as insulin deficiency worsens.
Anorectal carcinomas are associated with what infections in homosexual patients with HIV infection?
Human papillomavirus types 16 and 18. A CD4 count <500 is an independent risk factor. Cytological specimens of the anal canal are increasingly being used for screening and have been shown to have a high predictive value for dysplasia. Quadrivalent HPV vaccine against 6, 11, 16, and 18 has been approved by the FDA for immunization in males 9–26 years age to prevent anal cancer based on a randomized trial that included men who have sex with men, ages 16–26.
What are the most common causes of gastrointestinal bleeding in an AIDS patient?
The most common cause of upper GI bleeding is peptic ulcer disease. Lower GI bleeding is most commonly due to CMV colitis.
What is the most common cause of drug-induced hepatomegaly and abnormal liver tests with AIDS?
Medications, particularly sulfonamides and protease inhibitors.
An HIV patient on abacavir as part of the HAART therapy presents with fever, rash, and abdominal pain. What is the most likely diagnosis?
This is a hypersensitivity reaction to abacavir, described in 3%–8% of the patients taking the medication. This can be fatal and is more common in Caucasians and strongly associated with human leukocyte antigen (HLA)-B5701 haplotype.
What is the meaning of the term “lactic acidosis syndrome” in patients on HAART therapy?
This is a syndrome caused by nucleoside RTIs, most commonly stavudine, didanosine, and zidovudine. Progressive microvesicular steatosis occurs secondary to mitochondrial toxicity induced by these drugs. Clinical features include fatigue, abdominal pain, nausea or muscle aches, and hepatomegaly on physical examination along with abnormal liver enzyme tests. Metabolic acidosis and elevated arterial lactic acid levels greater than or equal to 5 mEq/L generally occur after 6 months of therapy and require discontinuance of the offending agent.
What potential metabolic disorder is associated with HAART therapy?
A lipodystrophy syndrome has been described consisting of peripheral fat loss (face, buttocks, and limbs) with central fat accumulation, gynecomastia, and hypertrophy of dosicervical fat pad (buffalo hump). This may also be associated with hypertriglyceridemia, insulin resistance, impaired glucose tolerance, lactic acidemia, and hepatic dysfunction. This may be due to toxic effects of protease inhibitors, particularly ritonavir, along with nucleoside RTI and nonnucleoside RTI.
What are the antiretroviral medications associated with abnormal liver tests?
• Raised aspartate aminotransferase (AST)/alanine aminotransferase (ALT):
Nucleoside RTI—stavudine, didanosine, abacavir
Nonnucleoside RTI—nevirapine, delaviridine, efavirenz
Protease inhibitors—tipranavir, lopinavir/ritonavir
• Indirect hyperbilirubinemia (clinically benign)
Protease inhibitors—atazanavir, indinavir
What risk factors for hepatotoxicity are associated with HAART therapy?
Up to 10% of patients receiving HAART therapy will develop Grade 3 or 4 hepatotoxicity.
• Use of ritonavir
• Increase in CD4 cell count >50 cells/mm3 during treatment
• Stage F3 and F4 fibrosis at the time of treatment
• Baseline elevation in serum aminotransferases
• Hepatitis C virus coinfection
What is the most common hepatic pathogen in AIDS?
MAC. The hallmark of this infection is poorly formed granulomas with acid fast staining organisms located within foamy macrophages.
True/False: Pneumocystis jiroveci can infect the liver in AIDS?
True. Isolated cases of P. jiroveci hepatitis have been described in patients on inhaled pentamidine, which fails to protect extrapulmonary sites from the pathogen.
What tumor seen in HIV infection is made up of spindle cells and originates from lymphatic endothelial cells?
Kaposi’s sarcoma (KS). In the alimentary tract, KS typically occurs as purplish, bulky gingival or palatal lesions, or gastrointestinal lesions. The vast majority are asymptomatic. Rarely, gastrointestinal KS can cause weight loss, abdominal pain, nausea and vomiting, upper or lower gastrointestinal bleeding, malabsorption, intestinal obstruction, and/or diarrhea. Treatment is reserved for symptomatic cases, mainly by instituting HAART. Advanced lesions can additionally be treated with liposomal doxorubicin or daunorubicin.
What percentage of patients with cutaneous KS have gastrointestinal or hepatic involvement?
33%. These are usually asymptomatic. In the pre-HAART era, the gastrointestinal tract was involved in approximately 40% of patients with KS at initial diagnosis and in up to 80% at autopsy. Involvement can occur in the absence of cutaneous disease.
A 43-year-old HIV-infected man complains of abdominal pain. He has fever, lymphadenopathy, skin angiomas, hepatomegaly, and lytic bone lesions. What is the most likely diagnosis?
Bacillary peliosis hepatis. Caused by Bartonella henselae, this infection causes dilated vascular lakes and blood filled spaces within the liver. It is the fourth leading cause of abnormal liver tests and hepatomegaly in AIDS patients. It is treated with erythromycin or doxycycline.
What are the six most common causes of abnormal liver tests and hepatomegaly in patients with AIDS?
Drug-induced, mycobacterial infection, CMV, Cryptosporidium, hepatitis C, and lymphoma.
What is AIDS cholangiopathy?
This syndrome resembles sclerosing cholangitis and papillary stenosis. Patients present with upper abdominal pain, diarrhea, and, less commonly, fever and jaundice. Labs reveal elevated serum alkaline phosphatase levels. Occasionally, transaminase elevations are also seen. This syndrome usually results from infection with Cryptosporidium. Other potential causative organisms include CMV and microsporidiosis. Rarely, this may be caused by MAC, Isospora belli, and Cyclospora cayetanensis.
True/False: The diagnosis of AIDS cholangiopathy is usually made by endoscopic retrograde cholangiopancreatography (ERCP).
True. ERCP most commonly demonstrates a combination of papillary stenosis and sclerosing cholangitis. Therapy is endoscopic sphincterotomy in the setting of stenosis with or without stenting of bile duct strictures. The role of magnetic resonance cholangiopancreatography (MRCP) for diagnosing AIDS cholangiopathy has not been fully evaluated. Ultrasound is often used as an initial diagnostic study and appears to have a high specificity for the condition.
How does the pattern of liver enzyme elevation assist in the diagnosis of HIV/AIDS-related disease?
The elevation of aminotransferases is nonspecific. The pattern and extent is not useful to correlate with a specific diagnosis. However, an impressive rise in the alkaline phosphatase without extra- or intrahepatic obstruction is strongly suggestive of infection with MAC.
True/False: HIV increases the risk of sexual transmission of the hepatitis C (HCV) virus.
True. HIV also increases the vertical transmission of HCV from mother to child.
What factors predict fibrosis and progression to cirrhosis in patients with hepatitis C who are also coinfected with HIV?
Older age at infection, higher ALT levels, higher levels of inflammatory activity, alcohol consumption of more than 50 g/d, and a CD4 count <500.
What is the most common cause of ascites in patients with AIDS?
Lymphoma. Other causes include tuberculosis, atypical mycobacterial infections, disseminated fungal infections, disseminated Pneumocystis, and non-AIDS-related causes.
True/False: Primary gastrointestinal fungal diseases are common in patients with HIV/AIDS.
False. Fungal infections typically occur as part of a disseminated infection causing chronic fever, anorexia, nausea, vomiting, hepatomegaly, and abnormal liver tests. Histoplasmosis and coccidiomycosis are among the more common infections seen.
A 37-year-old man with AIDS presents with severe anorectal pain associated with defecation. What is the most likely cause?
Ulceration of the anal canal, usually associated with HCV or CMV infection. Benign anorectal causes of anorectal pain including anal fissures and thrombosed hemorrhoids should be considered. The possibility of anal carcinoma should be considered.
What is the relationship between inflammatory bowel disease and AIDS?
An idiopathic colitis resembling ulcerative colitis that responds to steroid therapy has been described in patients with AIDS.
• • • SUGGESTED READINGS • • •
Wilcox CM, Saag MS. Gastrointestinal complications of HIV infection: changing priorities in the HAART era. Gut. 2008;57(6): 861-870.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 10, 2011;1-166. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed July 27, 2011.