http://depts.washington.edu/ghivaids/reslimited/case3/discussion.

html HIV Webstudy Case HIV with Diarrhea

A 43-year-old male inmate with stage C3 HIV/AIDS presents with loose, watery stools, abdominal cramping, sweats, fevers, poor appetite (2 months) and 15 lbs weight loss. He is taking Combivir one tablet bid and Nelfinavir 1,000 mg tid, and trimethoprim/sulfamethoxazole for secondary pneumocystis carinii pneumonia (PCP) prophylaxis. He reports good adherence, with an undetectable viral load and a CD4 count of 100 cells/mm3. He was diagnosed with HIV and PCP when he entered the U.S. from Mexico one year ago, at which time he had a CD4 count of 2 cells/mm3 and "high" HIV-1 viral load. He is an injecting drug user and has sex only with men. He reports unprotected sex with two anonymous partners two to three months ago when he traveled to Mexico. He weighs 130 lbs and is afebrile with normal blood pressure, genital and neurologic exam. His pharynx was without thrush; there was no scleral jaundice, some temporal wasting, no rash, abdominal tenderness, organomegaly, lymphadenopathy, or peripheral edema. Q: What is the differential diagnosis? A: Opportunistic pathogens such as disseminated Mycobacterium avium complex (MAC), PCP, andcytomegalovirus (CMV), should be considered, though PCP does not typically cause GI disease. He is also at risk for Entamoeba histolytica, Dientamoeba fragilis, Blastocystis hominis, Giardia lamblia, Campylobacter jejuni, Shigella spp, Salmonella spp, C. difficile, syphilis and herpes simplex virus. Because of recent travel to Mexico, Escherichia coli, Vibrio parahaemolyticus, Yersinia spp, rotaviruses, and Norwalk-like viruses are also in the differential. Additionally, this inmate could have diarrhea and wasting from HIV itself. It is not likely that Nelfinavir is causing his diahhrea as he tolerated this drug for nine to ten months and only recently developed diarrhea. Though the Nelfinavir may not be the cause of the diarrhea, it may be aggravating it.

Q: What tests should you perform/order? A: Stool samples should be sent for WBCs, to help differentiate inflammatory from non-inflammatory causes of diarrhea (history of watery as opposed to bloody diarrhea suggests non-inflammatory). Stool samples should also be sent for culture for enteric pathogens, smear for ova and parasites, Giardia antigen, Clostridium difficile toxins A and B, and acid-fast bacilli (AFB) smear and culture. Tests for ova and parasites, C. difficile toxins, and smears for AFB should be repeated twice, as it often takes multiple evaluations before some of these pathogens are detected. Blood should be sent for AFB culture and routine bacterial culture. If there is no temporal association of the onset of diarrhea with antiretroviral therapy and the stool and blood studies are negative, the next step in the evaluation is a colonoscopy. The highest yield for colonoscopy is typically in patients with fever, weight loss, and a CD4 count of fewer than 200 cells/mm3. Concentrated exam of the stool showed many cysts of Giardia lamblia and Entamoeba histolytica. This diagnosis should be reported to the local public health department. Many Entamoeba coli cysts, manyEndolimax nana cysts, and moderate Iodamoeba butschlii cysts were also seen. On auramine stain, moderate cryptosporidia were detected. Q: What treatment(s) should you offer this inmate? Are there drug-drug interactions to consider? A: Endolimax nana, Entamoeba coli, and Iodamoeba butschlii are nonpathogenic commensals and as such require no treatment. They are however markers of exposure to human feces and are often found in patients who are also infected with pathogenic organisms. Giardia and Entamoeba histolyticacan cause invasive disease and should generally be treated. The drug of choice for giardiasis is metronidazole 250 mg tid for seven days, which also has activity against E. histolytica. Unfortunately, there are no reliable therapies for Cryptosporidiosis, though paromomycin or nitazoxanide may have activity and offer benefit. Supportive care with hydration and nutrition, as well as institution of an effective antiretroviral regimen, are crucial aspects of care since improvement in the immune system often helps eradicate the infection. In immunocompetent hosts, cryptosporidiosis is usually self-limited. It may be in this inmate's best interest to change his medications to a more potent antiretroviral regimen in an effort to improve his T-cell response and minimize his gastrointestinal side effects. If the regimen is not changed, the dose of Nelfinavir should be changed to 1,250 mg po bid as this dose is easier to take and is associated with fewer loose stools compared to the tid dose. There are no known drug-drug interactions between metronidazole, paromomycin, or nitazoxanide and the antiretrovirals

he is currently taking. There is a drug-drug interaction between the oral solution form of the protease inhibitor amprenavir and metronidazole. This is not true for the capsule formulation of amprenavir. Q: What infection-control measures should you recommend? A: To minimize secondary transmission to others via fecal-oral spread, it is important to educate the inmate and staff on good hand-washing skills, particularly before and after meals and use of the restroom. He should be excluded from any kitchen work until his diarrhea has resolved and his stool is cleared of all organisms. Bethany Weaver, D.O., M.P.H., is Acting Instructor of Medicine at the University of Washington Center for AIDS & STD Research (CFAR) and Northwest Correctional Medicine Education Program. Disclosures: Stockholder, Pfizer.

References
1. Amadi B, Mwiya M, Musuku J, Watuka A, Sianongo S, Ayoub A, Kelly P. Effect of nitazoxanide on morbidity and mortality in Zambian children with cryptosporidiosis: a randomised controlled trial.Lancet. 2002 Nov 2;360(9343):1375-80. 2. Connolly GM, Foirbes A, Gazzard BG. Investigation of seemingly pathogen-negative diarrhea in patients infected with HIV1. Gut 1990;31:886-89. 3. DeHovitz JA, Pape JW, Boncy M, Johnson WD Jr. Clinical manifestations and therapy of Isospora belli infection in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1986;315:87-90. 4. Guerrant RL, Bobak DA. Bacterial and protozoal gastroenteritis. N Engl J Med 1991;325:327-40. 5. Guerrant RL, Thielman NM. Emerging enteric protozoa: Cryptosporidium, Cyclospora and microsporidia. In: Scheld WM, Armstrong D, Hughes JM, eds. Emerging Infections. Washington, DC: ASM Press; 1997:233-45. 6. Kotler DP, Francisco A, Clayton F, et al. Small intestinal injury and parasitic diseases in AIDS.Ann Intern Med. 1990;113:444-49. 7. Laughon BE, Druckman DA, Vernon A, et al. Prevalence of enteric pathogens in homosexual men with and without acquired immunodeficiency syndrome. Gastroenterology. 1988;94:984. 8. Oldfield EC III. Evaluation of chronic diarrhea in patients with human immunodeficiency virus infection. Rev Gastroenterol Disord. 2002 Fall;2(4):176-88. Review. 9. Pape JW, Verdier RI, Boncy M, et al. Cyclospora infection in adults infected with HIV. Clinical manifestations, treatment, and prophylaxis. Ann Intern Med. 1994;121:654-57. 10. Rossignol JF, Ayoub A, Ayers MS. Treatment of diarrhea caused by Cryptosporidium parvum: a prospective randomized, double-blind, placebo-controlled study of Nitazoxanide. J Infect Dis. 2001 Jul 1;184(1):103-6. 11. Rossignol JF, Hidalgo H, Feregrino M, Higuera F, Gomez WH, Romero JL, Padierna J, Geyne A, Ayers MS. A double-'blind' placebo-controlled study of nitazoxanide in the treatment of cryptosporidial diarrhea in AIDS patients in Mexico. Trans R Soc Trop Med Hyg. 1998 Nov-Dec;92(6):663-6. 12. Parasites and Parasitologic Resources of the Ohio State University www.biosci.ohio-state.edu/~parasite/.

Case 9: A 31-Year-Old Woman with AIDS and Cryptosporidiosis

Authors: Brian R. Wood, MDDavid H. Spach, MD

Learning Objectives
A 31-year-old HIV-infected woman presents with severe diarrhea and dizziness. She has long-standing HIV disease and her most recent CD4 count was 24 cells/mm3. For approximately 2 years, she has not taken any medications related to her HIV disease. The diarrhea began about 10 days ago and now she is having 10 to 15 watery stools per day, abdominal cramping, and nausea. Physical examination shows a thin female with a temperature of 38.1C, blood pressure of 86/60 mmHg, and minimal diffuse abdominal tenderness with deep palpation. A modified acid-fast stain on a stool sample is presumptively identified asCryptosporidium species (Figure 1). Which of the following is TRUE regarding diarrheal illness caused by Cryptosporidium in HIV-infected patients?

Most patients acquire Cryptosporidium from exposure to undercooked meat. Among antimicrobial agents studied for the treatment of cryptosporidiosis, the combination of azithromycin (Zithromax) plus paromomycin (Humatin) is the most effective therapy. Recommended treatment consists of high-dose trimethoprim-sulfamethoxazole (Bactrim, Septra). Immune restoration with antiretroviral therapy is considered essential in the management of patients with cryptosporidiosis. Ans Immune restoration with antiretroviral therapy is considered essential in the management of patients with cryptosporidiosis.

This answer is correct. Numerous antimicrobial agents have been studied for the treatment of cryptosporidiosis, but antimicrobial therapy generally provides only suppressive therapy at best. The recommended first-line treatment is restoration of the immune system with antiretroviral therapy. If antimicrobial therapy is used along with antiretroviral therapy, nitazoxanide is recommended

Discussion- Cryptosporidiosis
Background and Epidemiology
Cryptosporidium species are intracellular, spore-forming protozoan parasites that infect the epithelium of the gastrointestinaltract[1,2,3]. Ten species of Cryptosporidium exist, with most human infections caused by C. parvum and less frequently by C. hominis and C. meleagridis[1,2]. Infection with Cryptosporidium in immunocompetent persons often results in asymptomatic or mild self-limited disease, but in HIV-infected patients, particularly those with low CD4 counts, infection may result in chronic or life-threatening diarrhea, or extra-intestinal disease[1,2,4,5,6]. In developed countries, an estimated 14% of AIDS patients with diarrhea have Cryptosporidium infection[1]. Before the widespread use of HAART, Cryptosporidium oocysts (or spores) were detected in up to 4% of HIV-infected patients in the United States[5]. More recently, infection rates in developed countries have decreased dramatically, with a contemporary incidence of cryptosporidiosis amongst AIDS patients estimated at less than 1 per 100person-years[2].

Life Cycle and Transmission

Human infection occurs with ingestion of viable Cryptosporidium oocysts. After the oocysts are ingested, they release sporozoites, which then invade epithelial cells in the gastrointestinal tract, primarily in the small intestine (Figure 1)[1]. After entry into the epithelial cells, the sporozoites mature into trophozoites, which then reproduce in two cycles. In the asexual cycle the organism undergoes asexual reproduction (schizony), producing merozoites (type I), which are emitted into the lumen of the intestine and infect other gastrointestinal epithelial cells, thus multiplying and locally increasing the organism burden[3]. In the sexual cycle, some of the merozoites (type II) attach to epithelial cells, mature into gametocytes, which are fertilized in the intestinal tract, and then form into oocysts. The oocysts then release sporozoites that can either reinfect the intestinal epithelium and start the life cycle anew or be shed in feces, capable of infecting others[1]. The Cryptosporidium oocysts passed via feces may subsequently be transmitted by human-to-human or human-to-animal contact, or by consumption of contaminated drinking water[2,7]. Person-to-person transmission requires ingestion of as few as 10 to 100 oocysts, with transmission rates as high as 19% among household contacts of individuals with acute cryptosporidiosis[3]. Cattle and sheep are common animal reservoirs of the parasite[1].

Risk Factors
Patients at highest risk for cryptosporidiosis are those with a low CD4 count or some other source of immunosuppression[2]. Additional persons at risk for the disease include family members, sexual partners, and healthcare workers who are in contact with infected individuals[1]. A study that analyzed data from 6,913 HIV-infected patients in New Orleans from 1990 to 1998 identified three important risk factors for developing clinical infection: CD4 count less than 100 cells/mm 3, prior AIDS-defining illness, and age less than 35 years[8]. In this study, the investigators found that older age protected against development of cryptosporidiosis, possibly due to protective immunity from past exposures.

Clinical Manifestations
After an incubation period of 7 to 10 days, infection of the gastrointestinal tract by Cryptosporidium impairs absorption and enhances secretion, typically leading to watery, non-bloody diarrhea[1]. The duration and severity of disease depend on the host immune response, ranging from an asymptomatic or mild self-limited illness, to chronic low-level diarrhea, to a profuse choleralikeillness[1,5]. Patients with a strong Cryptosporidium serologic response and previous exposure(s) are more likely to have asymptomatic infection, though they may still shed oocysts in feces and be contagious[5]. Patients' CD4 cell counts are a strong predictor of whether they will develop self-limited or persistent disease. In a retrospective analysis, HIV-infected patients with self-limited cryptosporidiosis had a mean CD4 count of 312 cells/mm3 compared to those with persistent infection, who had a mean CD4 count of 57 cells/mm3 (Figure 2)[4]. This same report found that 87% of patients with a CD4 count less than 140 cells/mm3 who had cryptosporidiosis developed persistent disease. Patients with fulminant infection typically have a CD4 count less than 50 cells/mm3, and these patients rarely completely clear the infection, presumably because the organism can use the biliary tree as areservoir[1]. Fever occurs in up to one-third of patients, and abdominal cramping, nausea, weight loss, and malabsorption arecommon[1,2].

Extra-Intestinal Manifestations
Patients with advanced immunosuppression also have an increased risk for developing extra-intestinal disease, which usually occurs within the biliary tract, but case reports have documented infection in the lungs, stomach, pancreas, and middle ear[1]. When Cryptosporidium invades the epithelial cells of the biliary tract, the result may mimic primary sclerosing cholangitis, or lead to acalculous cholecystitis or papillary stenosis, which can cause pancreatitis[2,7]. Studies have revealed Cryptosporidium as the most commonly identified pathogen in cases of AIDS-related cholangiopathy[7]. Clinicians should consider this clinical entity in any HIV-infected patient presenting with fever, right upper quadrant abdominal pain, nausea, and vomiting.

Diagnosis
Diagnostic testing for Cryptosporidium should be performed in HIV-infected patients who develop acute diarrhea, chronic diarrhea, or biliary tract disease, especially if their CD4 count is less than 200 cells/mm 3. The easiest way to confirm the diagnosis is to identify oocysts with microscopic examination of stool or tissue. Routine ova and parasite testing does not detect Cryptosporidium.The[1] modified acid-fast stain, which stains the organism red, is the most common method used to detect Cryptosporidium on stool microscopic examination (Figure 3)[1,2]. Cryptosporidium can be differentiated from yeasts, which are similar size and shape but are not acid fast[2], and from other protozoan parasites, such as Cystoisospora (Isospora) belli and Cyclospora species, based on size (Figure 4)[3]. Patients with mild disease may require repeat stool testing due to the high false negative rates with low organism burden[2]. If modified acid fast staining is negative and clinical suspicion is high, direct immunofluorescence microscopy (Figure 5) and ELISA testing of stool have greater sensitivity and specificity[1,2]. Serologic testing of blood generally does not help in making the diagnosis, mainly because exposure to Cryptosporidium is common and healthy persons who do not have active disease may test positive[2]. Endoscopy is often normal, but patients with severe disease may have reduction of duodenal folds secondary to villous atrophy[7]. Hematoxylin and eosin stains or light microscopy may be performed from mucosal biopsies (Figure 6)[7] .If a patient demonstrates symptoms of biliary tract disease, an ultrasound is often the first test of choice, but endoscopic retrograde cholangiopancreatography (ERCP) is more sensitive[7].

General Approach to Treatment

Patients who are asymptomatic or have intact immune function generally do not require treatment for cryptosporidiosis. The primary treatment for AIDS patients with symptomatic cryptosporidiosis is to restore immune function with effective antiretroviral therapy (Figure 7 and Figure 8)[1,6,7]. Cell-mediated immunity is vital for protection against cryptosporidiosis, and in many cases, an increase in CD4 count to greater than 100 cells/mm3 may result in resolution of symptoms[2]. Patients with Cryptosporidiuminfection and CD4 cell counts greater than 350 likely will have a self-limited illness, but may benefit from antimicrobial therapy. Several antimicrobial agents have been studied for the treatment of cryptosporidiosis in HIV-infected patients, including nitazoxanide (Alinia), paromomycin (Humatin), and azithromycin (Zithromax). No antimicrobial agent, however, has been shown to be reliably effective against Cryptosporidium in the absence of antiretroviral therapy. When antimicrobial therapy is used in combination with antiretroviral therapy, nitazoxanide is the recommended agent[2]. Since patients with severe cryptosporidiosis typically have clinically-significant dehydration, supportive care with fluid rehydration and electrolyte repletion is an important component of therapy. Antimicrobial therapy has not been reliably effective against AIDS cholangiopathy, so if biliary disease is present, endoscopic therapy may be necessary. Specific interventions consist of sphincterotomy for papillary stenosis (which relieves cholangitis and may relieve pain, but does not improve survival), or cholecystectomy for cholecystitis (which does not clear the organism, indicating there may be a hepatic reservoir)[7].

Antimicrobial Agents
Nitazoxanide: The antimicrobial nitazoxanide is typically well tolerated with minimal drug interactions, and although good data exist for its effectiveness in immunocompetent patients with cryptosporidiosis, data in the HIV-infected population are mixed. In a compassionate use study in 2006 that used nitazoxanide 500 to 1500 mg twice daily in 365 AIDS patients for median 62 days, 59% of subjects had a sustained clinical response (sustained improvement in the patient's global assessment of gastrointestinal symptoms)[9]. A double-blind, placebo-controlled study of nitazoxanide in patients with AIDS randomized participants to nitazoxanide 500 mg twice daily, 1000 mg twice daily, or placebo for 14 days; the patients then crossed over to a different group based on random assignment. Participants who received the drug at either dose had higher rates of parasite eradication from stool samples than patients treated with placebo, and 19 of 22 patients whose stool was cleared of the parasite experienced resolution of their diarrheal symptoms (Figure 9)[10]. In contrast, a 2007 systematic review and analysis of

cryptosporidiosis treatment in HIV-infected patients found that nitazoxanide without antiretroviral therapy provided minimal benefit in controlling diarrhea or in reducing oocyst clearance when compared with placebo[6]. Therefore, nitazoxanide may be used for the treatment of cryptosporidiosis, but it is not a substitute for effective antiretroviral therapy[2]. Paromomycin: Although paromomycin is not FDA-approved for the treatment of cryptosporidiosis, data from animal models suggest high-dose paromomycin has significant activity against Cryptosporidium[2]. In addition, studies have demonstrated initial response rates to be as high as 67% in humans, but frequent relapses cause long-term response rates to be as low as 33%[2]. Success rates are even lower in patients with CD4 counts less than 100 cells/mm3[2]. In one randomized controlled trial that compared paromomycin 500 mg four times daily for 21 days with placebo in 35 HIV-infected adults with a CD4 count less than or equal to 150 cells/mm3 (median 24 cells/mm3), response rates between the paromomycin and placebo arms did not show a statistically significant difference; the investigators concluded that paromomycin monotherapy was ineffective (Figure 10)[11]. Therefore, paromomycin is not recommended as monotherapy for cryptosporidiosis[2]. Azithromycin: In a small study, 13 HIV-infected patients with symptomatic cryptosporidiosis received azithromycin therapy, at doses ranging from 500 to 1500 once daily for 20 to 50 days[12]. Nine of the 13 patients had a good clinical and parasitologic response. A trial from India examined the efficacy of azithromycin (500 mg for 5 to 14 days) in 41 HIV-infected patients with Cryptosporidium infection[13]. Most of these patients, however, had asymptomaticCryptosporidium infection. Among the 13 symptomatic patients, all had symptomatic improvement (50% reduction in baseline stool frequency with a feeling of well-being) after 5 days of azithromycin 500 mg once daily, but only 5 of the patients had clearance of Cryptosporidium oocysts from stool. Paromomycin plus Azithromycin: A small study involving 14 patients with a CD4 counts less than or equal to 100 cells/mm3 (median 30 cells/mm3) demonstrated reduced oocyst excretion and some clinical improvement with a 28-day course of paromomycin 1g twice daily plus azithromycin 600 mg once daily followed by paromomycin alone x 12weeks[14].

Summary Treatment Recommendations

The primary and preferred therapy for symptomatic cryptosporidiosis in HIV-infected patients with advanced immunosuppression is restoration of the immune system with antiretroviral therapy combined with supportive care, including rehydration and replacement of electrolytes. Nitazoxanide is considered a second-line or complementary agent for severe cases when used in combination with antiretroviral therapy, and paromomycin plus azithromycin should be considered only if these fail. Anti-motility agents like loperamide and tincture of opium may help to improve symptoms and rates of electrolyte loss, but are not effective treatment. For patients with cryptosporidiosis-related biliary disease, expert consultation is recommended

References
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1. Chen XM, Keithly JS, Paya CV, LaRusso NF. Cryptosporodiosis. N Engl J Med. 2002; 346:1723-31. [PubMed Abstract] 2. Kaplan JE, Benson C, Holmes KH, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009;58(RR-4):1-207. [PubMed Abstract] 3. Goodgame, RW. Understanding intestinal spore-forming protozoa: cryptosporidia, microsporidia, isospora, cyclospora. Ann Intern Med. 1996;124:429-41. [PubMed Abstract] 4. Flanigan T, Whalen C, Turner J, Soave R, Toerner J, Havlir D, Kotler D. Cryptosporidium infection and CD4 counts. Ann Intern Med. 1992;116:840-2. [PubMed Abstract] 5. Frost FJ, Tollestrup K, Craun GF, Fairley CK, Sinclair MI, Kunde TR. Protective immunity associated with a strong serological response to a Cryptosporidium-specific antigen group, in HIV-infected individuals. J Infect Dis. 2005;192:61821. [PubMed Abstract]

6. Abubakar I, Aliyu SH, Arumugam C, Usman NK, Hunter PR. Treatment of cryptosporidiosis in immunocompromised individuals: systematic review and meta-analysis. Br J Clin Pharmacol. 2007;63:387-93. [PubMed Abstract] 7. Chen XM, LaRusso NF. Cryptosporidiosis and the pathogenesis of AIDS-cholangiopathy. Semin Liver Dis. 2002;22:277-89. [PubMed Abstract] 8. Inungu JN, Morse AA, Gordon C. Risk factors, seasonality, and trends of cryptosporidiosis among patients infected with human immunodeficiency virus. Am J Tr Med Hyg. 2000;62:384-7. [PubMed Abstract] 9. Rossignol JF. Nitazoxanide in the treatment of acquired immune deficiency syndrome-related cryptosporidiosis: results of the United States compassionate use program in 365 patients. Aliment Pharmacol Ther. 2006;24:887-94. [PubMed Abstract] 10. Rossignol JF, Hidalgo H, Feregrino M et al. A double-blind placebo-controlled study of nitazoxanide in the treatment of cryptosporidial diarrhea in AIDS patients in Mexico. Trans R Soc Trop Med Hyg. 1998;92:663-6. [PubMed Abstract] 11. Hewitt RG, Yiannoutsos CT, Higgs ES, et al. Paromomycin: no more effective than placebo for treatment of cryptosporidiosis in patients with advanced human immunodeficiency virus infection. AIDS Clinical Trial Group. Clin Infect Dis. 2000;31:1084-92. [PubMed Abstract] 12. Dionisio D, Orsi A, Sterrantino G, et al. Chronic cryptosporidiosis in patients with AIDS: stable remission and possible eradication after long-term, low dose azithromycin. J Clin Pathol. 1998;51:138-42. [PubMed Abstract] 13. Kadappu KK, Nagaraja MV, Rao PV, Shastry BA. Azithromycin as treatment for cryptosporidiosis in human immunodeficiency virus disease. J Postgrad Med. 2002;48:179-81. [PubMed Abstract] 14. Smith NH, Cron S, Valdez LM, Chappell CL, White AC Jr. Combination drug therapy for cryptosporidiosis in AIDS. J Infect Dis. 1998;178:900-3. [PubMed Abstract]

This figure is from Chen XM, Keithly JS, Paya CV, LaRusso NF. Cryptosporidiosis. N Engl J Med. 2002; 346:1723-31. Reproduced with permission from the Massachusetts Medical Society. Copyright 2002 Massachusetts Medical Society. All rights reserved.

Modified Acid-fast Staining of Stool Samples Showing Cryptosporidium Oocysts

Updated April 3, 2008

Case 8: A 27-Year-Old Man with AIDS and Disseminated Histoplasmosis

Authors: Brian R. Wood, MDDavid H. Spach, MD

Learning Objectives
A 27-year-old man from Mexico with newly diagnosed HIV (CD4 count 7 cells/mm3 and HIV RNA greater than 1 million copies/ml) presents to the clinic with 4 weeks of fever, chills, night sweats, myalgias, dry cough, nausea, vomiting, and diarrhea. He has watery bowel movements 1-2 hours after eating, and has lost 25 lbs in the last 4 weeks. He recently had a negative tuberculin skin test. Initial evaluation shows hypoxia evident on an arterial blood gas and a chest radiograph with diffuse hazy opacities (Figure 1). He is initially treated for presumptive Pneumocystis pneumonia and atypical pneumonia. Two weeks later, however, fungal blood cultures show growth of hyphal elements identified as Histoplasma capsulatum and thus he is diagnosed with progressive disseminated histoplasmosis. Which of the following is True about this patients treatment?

The preferred initial therapy for HIV-infected patients with progressive severe disseminated histoplasmosis is itraconazole (Sporanox)

If the patient does not tolerate itraconazole for maintenance therapy, fluconazole (Diflucan) can be used and expected to have the sa relapse. For patients taking itraconazole maintenance therapy, serum itraconazole levels should be monitored, at least initially.

During maintenance therapy, obtaining Histoplasma antigen levels is not recommended because they have no value in monitoring for You answered:

For patients taking itraconazole maintenance therapy, serum itraconazole levels should be monitored, at least initially.

This answer is correct. Monitoring serum itraconazole levels during maintenance therapy is recommended, and although required l patients should generally have a random serum itraconazole level of at least 1.0 g/mL. Achieving serum itraconazole levels greater leads to greater toxicity.

Figure 1. Chest Radiograph of AIDS Patient with Disseminated Histoplasmosis

This chest radiograph shows diffuse pulmonary infiltrates in an AIDS patient with disseminated histoplasmosis.

Discussion - Disseminated Histoplasmosis

Background and Epidemiology

Histoplasma capsulatum is a dimorphic fungus that grows as a mold at temperatures less than 35C and as a yeast at temperatures g with bird or bat guano serves as the main environmental reservoir, so this fungus is often present in or near chicken coops and caves humans in the Americas is Histoplasma capsulatum var capsulatum[2]. Histoplasmosis is the most common endemic mycosis affectin States, with an estimated incidence of 2 to 5% among patients from endemic regions[3]. and up to 25% in hyperendemic cities [4]. Mississippi river valleys of the United States and many areas of Central and South America; cases have also been reported in Europe,

Pathogenesis and Risk Factors

Histoplasmosis occurs in humans when microconidia are inhaled and transformed into yeast in the lungs[1]. Clinical disease can resu reactivation of prior infection[5]. The risk and severity of illness depend on the number of conidia inhaled and the cellular immunity o increases dramatically with CD4 count less than 50 cell/mm3[6], and 90% of cases occur with a CD4 count less than 200 cells/mm3. H macrophages, which facilitatesdissemination[1]. Macrophages from HIV-infected patients, especially those with low CD4 cell counts, h

and bind the yeast and allow more intracellular growth[7]. Therefore, patients with HIV are more susceptible to histoplasmosis becau and defective macrophage activity[7].

Clinical Manifestations

Histoplasma infection can be asymptomatic or symptomatic, acute or chronic, and focal or disseminated[8]. Immunocompetent indiv localized to the lungs. In HIV-infected patients, disseminated disease often develops, particularly in those who have a CD4 count less example, in one outbreak in Indianapolis, 95% of patients with AIDS who developed histoplasmosis developed disseminated disease[ HIV-infected patients from 1990 to 1993 in Kansas City, 74% of patients with histoplasmosis had symptomatic disease, and 100% of disseminated disease[5]. Untreated disseminated disease usually progresses in an indolent manner over 1 to 3 months, but can be a typically present with nonspecific symptoms such as fever, fatigue, anorexia, and weight loss[2]. Approximately 50% of cases include radiography often shows diffuse or patchy opacities that can mimic Pneumocystis pneumonia, as in the case presented. Less often, th infiltrates, nodules, or cavities. Patients may also have hepatosplenomegaly (25%), lymphadenopathy (25%), sepsis (10 to 20%), ce (10 to 20%), or gastrointestinal involvement (10 to 20%)[1]. Central nervous system involvement portends a poor prognosis and mo lymphocytic meningitis. Disease can occur anywhere along the gastrointestinal tract and may cause diarrhea, abdominal pain, obstru manifestations are present in about 10% of patients and can be papular, maculopapular or pustular in nature, or can occur in the form multiforme, eczematous rash, or rosacea-like rash[1]. Mucosal lesions occur more often with disseminated histoplasmosis than in mo include superficial ulcerations, deep ulcerations, nodular masses or verrucous lesions of the lips, tongue, gingival pharynx or larynx[2 affect the adrenal glands than other endemic mycoses, leading to adrenal insufficiency in a number of cases[2]. Common laboratory histoplasmosis include anemia, leucopenia, thrombocytopenia, elevated alkaline phosphatase, elevated erythrocyte sedimentation rat lactate dehydrogenase (LDH)[2].

Diagnosis

Possible diagnostic methods for histoplasmosis include culture, fungal stains (of body fluids or tissues), serologic testing, and antigen patients, the sensitivity of serologic tests ranges from 85 to 100%, depending on the type ofHistoplasma infection. Immunocomprom histoplasmosis, however, often do not mount a robust antibody response and thus have high false-negative rates with serologic testin disseminated disease with a large fungal load, culture and antigen detection are generally preferred in this setting[10]. The sensitivit disseminated histoplasmosis in AIDS patients is approximately 85% (Figure 1)[1]. In a study that examined antigen testing of samp histoplasmosis during a 5-year period in Indianapolis, antigen testing of urine had the highest yield (95%), followed by serum (86%) bronchoalveolar lavage fluid (70%) (Figure 2)[1]. For patients with localized pulmonary disease, antigen testing has poor sensitivity disseminated disease, it remains the most sensitive test available[3,10]. Antigen detection has a specificity greater than 98%, and re (compared with culture, which typically takes 2 to 4 weeks to turn positive)[1]. Antigen cross-reactivity can occur with coccidioidomy paracoccidioidomycosis, but often these can be differentiated by history and epidemiology. In some patients with disseminated diseas show yeasts present withinneutrophils[2]. Skin biopsy can provide the fastest diagnosis in patients who have skin disease. In patient marrow biopsy can be useful and may give a diagnosis more rapidly than antigen testing. Overall, given the significant false-negative method, most experts recommend sending a combination of tests.

Indications for Treatment

The indications for treatment are summarized in the Clinical Practice Guidelines for the Management of Patients with Histoplasmosis: Diseases Society of America (IDSA) (Figure 3)[11]. Treatment for histoplasmosis is not generally indicated in mild disease that lasts above, however, most HIV-infected patients suffer from disseminated disease, and treatment in these cases is always indicated as it without treatment, progressive disseminated histoplasmosis is usually fatal[2]. Treatment is also indicated (with good evidence) for m chronic pulmonary, and central nervous system disease. Though treatment recommendations exist for mild acute pulmonary disease severe and persistent mediastinal lymphadenitis, and symptomatic mediastinal granuloma, evidence for these recommendations are IDSA guidelines and have not been definitively proven[11].

Treatment for Disseminated and Central Nervous System Disease

Treatment regimens for histoplasmosis vary depending on the type and severity of disease. The following treatment recommendation IDSA guidelines for the management of patients with histoplasmosis; these recommendations are not specific to persons with HIV inf moderate to severe progressive disseminated infection, the recommended therapy consists of liposomal amphotericin B (AmBisome) itraconazole (Sporanox) for at least 12 months. The itraconazole capsules or solution may be used, but the capsules should be avoide 2 receptor blocker or a proton pump inhibitor. Use of amphotericin B lipid complex (Abelcet) may be preferred in some patients becau In addition, deoxycholate amphotericin B is considered a less expensive possible alternative to lipid formulations of amphotericin and low-risk for nephrotoxicity[11].

The preference for liposomal amphotericin B is based on a 2002 study involving AIDS patients with moderately severe to severe disse liposomal amphotericin B was associated with greater efficacy and less toxicity than amphotericin B deoxycholate (Figure 5)[13]. Itr initial therapy for patients with moderate to severe disseminated disease based on data that deoxycholate amphotericin B leads to gr cultures than itraconazole (85% versus 53% at 2 weeks), more robust decline in serum antigen levels (1.6 versus 0.1 units at 2 wee levels (2.1 versus 0.2 units at 2 weeks)[12]. For patients with mild to moderate progressive disseminated histoplasmosis, itraconazo is recommended [11]. Patients with central nervous system histoplasmosis should receive high-dose liposomal amphotericin B for 4 t itraconazole for at least 12 months.

Treatment for Pulmonary Disease

The first-line recommendation for moderate to severe acute pulmonary histoplasmosis is intravenous liposomal amphotericin B (Amb oral itraconazole for 12 weeks. A 1 to 2 week course of intravenous methylprednisolone is recommended for patients who develop re severe hypoxemia[11]. If disease is mild but persists for longer than 4 weeks, itraconazole is effective (6 to 12 weeks of therapy if di disseminated). The recommendations for treatment of patients with histoplasmosis manifesting as chronic cavitary pulmonary disease nodules, mediastinal disease, pericarditis, or rheumatologic disease are not discussed here but are provided in detail in the 2007 IDS

Alternative Antifungal Agents for Treatment of Histoplasmosis

Fluconazole (Diflucan) has been used to treat histoplasmosis, but studies have shown high rates of relapse and development of resist when other therapies fail. Ketoconazole (Nizoral) is not generally used because of higher rates of side effects compared with itracona "azole" drugs, posaconazole (Noxafil) and voriconazole (Vfend) both show in vitro activity against histoplasma; a 2006 study, howeve fluconazole induces cross-resistance to voriconazole[14]. small case series including six patients with severe histoplasmosis who had promising results using posaconazole for salvage therapy, but more studies with this drug are needed[15]. Therefore, fluconazole, ke voriconazole are all considered as second-line agents forhistoplasmosis[11]. Echinocandins are not recommended for the treatment o

Monitoring Patients on Therapy

Because serum levels of itraconazole vary significantly based on absorption, the formulation used (levels are generally higher with th drug interactions, levels should be checked 2 weeks after initiation of therapy or any dose change. Checking levels can also help whe treatment failure. The exact target level has not been defined, but according to the 2007 IDSA guidelines, it is generally recommende serum itraconazole level of at least 1.0 mcg/mL to prevent treatment failure. Levels greater than 10 mcg/mL are unnecessary and lik serum itraconazole levels do not vary significantly throughout a 24-hour period, the timing of the blood draw in relation to the last itr important and thus random levels are acceptable[11]. Histoplasma antigen levels can be used to follow the effect of treatment and monitor for relapse. Both serum and urine antigen concentrations decrease throughout the course of therapy, eventually to undetectable levels, although this may take

more than a year if the fungal burden is high. If antigen concentrations do not decline with treatment, one should suspect non-adher treatment failure[10]. Antigen levels should be checked before treatment is initiated, at 2 weeks, at 1 month, then every 3 months d monitoring of antigen levels should continue for 6 to 12 months after therapy has ended, and any time treatment failure or relapse is approximately 90% ofrelapses[11]. In a patient who previously had a decrease in antigen concentration with treatment, a 2-unit or g concentration suggests relapse (a 4-unit or greater increase is more sensitive)[10].

Discontinuing Maintenance Therapy

Traditionally,it was thought that lifelong maintenance therapy was required for all AIDS patients with histoplasmosis to prevent relap that patients with AIDS who have a sustained immunologic response to antiretroviral therapy may safely discontinue histoplasmosis t 2004 followed 32 patients after at least 12 months of antifungal therapy for histoplasmosis and at least 6 months of HAART[16]. All h disease and CD4 counts greater than 150 cells/mm3. There were no relapses after two years of follow-up[16]. Therefore, the 2007 ID patients with disseminated histoplasmosis who are on HAART can safely discontinue itraconazole therapy if the following conditions a at least 12 months of itraconazole therapy, (2) fungal blood cultures are negative, (3) serum and urine antigen levels are less than 4 assays), and (4) CD4 count is greater than 150 cells/mm3. Nevertheless, patients require lifelong suppressive therapy with itraconazo relapse (which occurs in 10-15% of cases), fail HAART, or if their CD4 count decreases to less than 150 cells/mm3[11]. The IDSA gui practice of discontinuing therapy is common, the evidence behind it is limited.

Role of Initiating Antiretroviral Therapy

Starting HAART in patients with disseminated histoplasmosis is important because it is associated with better responses to antifungal with histoplasmosis who were taking HAART had much better response rates to antifungal therapy (95.5% versus 47.4%) and lower documented cases of immune reconstitution inflammatory syndrome (IRIS) in patients with histoplasmosis, but it is rare and usually delayed for that reason[11]. Drug-drug interactions are an important consideration when starting HAART in a patient on antifungal th drug-drug interaction may occur between itraconazole and efavirenz (Sustiva, also contained in Atripla). In one case report, this com levels, and the patient developed an increase in urine histoplasma antigen levels. Increasing the dose of itraconazole did not overcom histoplasma antigen levels only decreased after the patient switched to a protease-inhibitor based antiretroviral regimen[17]. On the as lopinavir-ritonavir (Kaletra) or atazanavir (Reyataz) plus ritonavir (Norvir) can have the opposite effect, causing increased levels o

References
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1. Wheat J. Endemic mycoses in AIDS: a clinical review. Clin Microbiol Rev. 1995;8:146-59. [PubMed Abstract]

2. Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev. 2007;20:115-32. [PubMed Abstract]

3. Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-infected adults and adolescents: rec National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. MMWR Recomm Rep. [Centers for Disease Control and Prevention - Accessed February 10, 2008] 4. Wheat J. Histoplasmosis in the acquired immunodeficiency syndrome. Curr Top Med Mycol. 1996;7:7-18. [PubMed Abstract]

5. McKinsey DS, Spiegel RA, Hutwagner L, et al. Prospective study of histoplasmosis in patients infected with human immunode and pathophysiology. Clin Infect Dis. 1997;24:1195-203. [PubMed Abstract]

6. Tobn AM, Agudelo CA, Rosero DS, et al. Disseminated histoplasmosis: a comparative study between patients with acquired i human immunodeficiency virus-infected individuals. Am J Trop Med Hyg. 2005;73:576-82. [PubMed Abstract]

7. Chaturvedi S, Frame P, Newman SL. Macrophages from human immunodeficiency virus-positive persons are defective in host capsulatum. J Infect Dis. 1995;171:320-7. [PubMed Abstract]

8. Couppi P, Sobesky M, Aznar C, et al. Histoplasmosis and acquired immunodeficiency syndrome: a study of prognostic factors [PubMed Abstract]

9. Wheat LJ, Chetchotisakd P, Williams B, Connolly P, Shutt K, Hajjeh R. Factors associated with severe manifestations of histop 2000;30:877-81. [PubMed Abstract] 10. Wheat J. Current diagnosis of histoplasmosis. Trends Microbiol. 2003;11:488-94. [PubMed Abstract]

11. Wheat LJ, Freifeld AG, Kleiman MB, Baddley JW, McKinsey DS, Loyd JE, Kauffman CA; Infectious Diseases Society of America management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis. 200 [PubMed Abstract] 12. Wheat LJ, Cloud G, Johnson PC, Haddad N, Le Monte A, Brizendine E, Hafner R. Clearance of fungal burden during treatment liposomal amphotericin B versus itraconazole. Antimicrob Agents Chemother. 2001;45:2354-7. [PubMed Abstract]

13. Johnson P, Wheat LJ, Cloud G, et al. Safety and efficacy of liposomal amphotericin B compared with conventional amphoterici histoplasmosis in patients with AIDS. Ann Intern Med. 2002;137:105-9. [PubMed Abstract]

14. Wheat LJ, Connolly P, Smedema M, et al. Activity of newer triazoles against Histoplasma capsulatum from patients with AIDS Chemother. 2006;57:1235-9. [PubMed Abstract] 15. Restrepo A, Tobon A, Clark B, et al. Salvage treatment of histoplasmosis with posaconazole. J Infect. 2007;54:319-27. [PubMed Abstract]

16. Goldman M, Zackin R, Fichtenbaum CJ, et al. Safety of discontinuation of maintenance therapy for disseminated histoplasmos antiretroviral therapy. Clin Infect Dis. 2004;38:14859. [PubMed Abstract]

17. Koo HL, Hamill RJ, Andrade RA. Drug-drug interaction between itraconazole and efavirenz in a patient with AIDS and dissemi 2007;45(6):e77-9. [PubMed Abstract]

18. Crommentuyn KM, Mulder JW, Sparidans RW, Huitema ADR, Schellens JHM, Beijnen JH. Drug-drug interaction between itraco lopinavir/ritonavir in an HIV1infected patient with disseminated histoplasmosis. Clin Infect Dis. 2004;38:e735. [PubMed Abstract]

Figure 1. Estimated Sensitivities of Diagnostic Tests for Disseminated Histoplasmosis in Patients with AIDS

This table shows a comparison of four different tests used to diagnose histoplasmosis in patients with AIDS who have di Adapted from: Wheat J. Endemic mycoses in AIDS: a clinical review. Clin Microbiol Rev. 1995;8:146-59.

Figure 2. Comparison of Histoplasma Antigen Detection Tests in Different Body Fluids in Patients with AIDS and Dissem

Abbreviations: CSF = cerebrospinal fluid; BAL = bronchoalveolar fluid.

This graph shows a comparison of different Histoplasma antigen tests for the diagnosis of histoplasmosis in patients with histoplasmosis. In this figure, n represents the number of patients tested. Adapted from: Wheat J. Endemic mycoses in AIDS: a clinical review. Clin Microbiol Rev. 1995;8:146-59. Wheat J. End review. Clin Microbiol Rev. 1995;8:146-59. Figure 3. Indications for Antifungal Treatment for Different Manifestations of Histoplasmosis

This table is based on the recommendations from the 2007 IDSA guidelines for the management of patients with histopl

Adapted from: Wheat LJ, Freifeld AG, Kleiman MB, Baddley JW, McKinsey DS, Loyd JE, Kauffman CA; Infectious Disease practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society 2007;45:807-25. Figure 4. Recommendations for the Treatment of Severe Manifestations of Histoplasmosis

Figure 5. Comparison of Liposomal Amphotericin B and Conventional Amphotericin B for Induction Therapy of Histoplas

This randomized, double-blinded trial involved 81 patients with AIDS and moderate to severe disseminated histoplasmo 2:1 ratio to receive intravenous liposomal amphotericin B (AmBisome) 3 mg/kg/d or conventional amphotericin B 0.7 m patient who had successful induction therapy, then received itraconazole for 10 weeks as consolidation therapy. As show received liposomal amphotericin B had higher clinical efficacy of induction therapy (P = 0.014) and less nephrotoxicity (P those who received conventional amphotericin B.

Data from: Johnson P, Wheat LJ, Cloud G, et al. Safety and efficacy of liposomal amphotericin B compared with convent therapy of histoplasmosis in patients with AIDS. Ann Intern Med. 2002;137:105-9.

Case 4: Fluconazole-Resistant Oropharyngeal Candidiasis

Author: David H. Spach, MD

Learning Objectives

A 43-year-old HIV-infected woman presents to the clinic with oral candidiasis that is clinically not responding to fluconazole (Diflucan advanced immune suppression with a CD4 count of 22 cells/mm3 and HIV RNA of 46,340 copies/ml. She is taking a 5-drug salvage a trimethoprim-sulfamethoxazole (Bactrim, Septra), azithromycin (Zithromax), and fluconazole. She has taken fluconazole on and off f oropharyngeal candidiasis and the past 3 months she had taken fluconazole 200 mg PO once daily. She currently denies any esophag Which of the following is true regarding fluconazole-resistant oral candidiasis in HIV-infected patients?

The most important risk factor identified for the development of fluconazole-resistant oropharyngeal candidiasis is sulfamethoxazole for longer than 60 days.

Fluconazole exerts its effect by inhibiting fungal cell wall synthesis. Fluconazole resistance in Candida species occu increase production in cell wall precursors.

More than 95% of Candida albicans isolates from patients with fluconazole-refractory oropharyngeal candidiasis sh (Sporanox). Fewer than 5% of patients with fluconazole-refractory oropharyngeal candidiasis will respond to itrac 200 mg per day.

Major identified risk factors for the development of fluconazole-resistant candidiasis include low CD4 cell count an

Major identified risk factors for the development of fluconazole-resistant candidiasis include low CD4 cell count and cumulative f An s

This answer is correct. The most important risk factors identified related to the development of fluconazole-resistant candidiasis include low CD4 cell count, greater number of fluconazole-treated episodes, and longer median duration of fluconazole therapy. Fluconazole resistance can involve an alteration in the target enzyme 14-alpha demethylase (change in binding site or over expression of the enzyme) or enhanced drug efflux caused by plasma membrane transporters. Many strains have developed multiple resistance mechanisms.

Case 4: Discussion
Epidemiology and Risk Factors
During the 1980s and 1990s, numerous reports emerged describing the development of refractory oropharyngeal candidiasis in AIDS patients following prolonged exposure to fluconazole (Diflucan)[1]. The emergence of fluconazole-resistant candidiasis in HIV-infected persons correlated with the widespread use of fluconazole for oropharyngeal candidiasis during this time period. During the 1980s and 1990s, the percentage of fluconazole-resistant Candida species ranged from approximately 5 to 33%[1,2]. In addition, following the widespread use of fluconazole, the proportion of C. albicans isolates decreased and other Candida species, including C. krusei, C. dubliniensis, and C. glabrata, increased. Fluconazole-resistant oropharyngeal candidiasis has involved both C. albicans and the non-albicans species. From a clinical standpoint, treatment-refractory candidiasis is defined as signs and symptoms of candidiasis that persist for longer than 7 to 14 days after appropriate therapy[3]. Investigators have identified low CD4 cell count, advanced immunosuppression, greater number of fluconazole-treated episodes, and longer median duration of fluconazole therapy as the most important risk factors[3,4,5,6]. In more recent years, clinicians have observed a major decrease in the frequency of fluconazole-resistant oropharyngeal candidiasis, predominantly as a result of the widespread use of potent combination antiretroviral therapy[7]. Nevertheless, treatment refractory oropharyngeal candidiasis still occurs in approximately 5% of HIV-infected persons[3].

Mechanisms for Fluconazole Resistance

Ergosterol is the predominant sterol in the fungal membrane and it serves as a bioregulator of fungal membrane fluidity andintegrity[8]. The synthesis of ergosterol requires multiple steps and multiple enzymes (Figure 1). Fluconazole exerts its action on the fungal membrane by inhibiting the fungal cytochrome P-450 enzyme 14 alpha-demethylase, thereby blocking the conversion of lanosterol to ergosterol (Figure 2)[6]. The inhibitory action of fluconazole causes depletion of ergosterol which in turn alters the fungal membrane structure and function. The inhibition of 14 alpha-demethylase also results in the build-up of lanosterol and other ergosterol precursors. The alterations in the fungal cell membrane eventually lead to fungal cell death. The selective action of fluconazole for fungal cell membranes occurs because human cells use cholesterol, not ergosterol, for the synthesis of cell membranes. The echinocandins have a mechanism of action distinct from the azoles: these agents inhibit fungal cell wall synthesis by blocking the production of 1,3-beta-D-glucan. Resistance to fluconazole can develop as a result of an alteration in the target enzyme 14 alpha-demethylase (change in binding site or over expression of the enzyme) (Figure 3) or from enhanced drug efflux caused by plasma membrane transporters (Figure 4)[6,7,9,10,11]. Many of the strains of fluconazole-resistant Candida species display multiple mechanisms of resistance[7].

Definition of Fluconazole Resistance

In 2008, the Subcommittee for Antifungal Testing of the Clinical Laboratory Standards Institute (CLSI) defined breakpoints for antifungal agents active against Candida species. Isolates with a fluconazole MIC less than 8 mcg/ml are classified as sensitive (S), those with 16 to 32 mcg/ml as dose-dependent sensitive (S-DD), and those with greater than or equal to 64 mcg/ml are resistant[12,13]. Primary fluconazole resistance is defined as resistance in the absence of prior fluconazole exposure. Secondary resistance occurs as a result of treatment with fluconazole. Clinical failure refers to persistence or progression of oropharyngeal candidiasis despite antifungal therapy. Factors that can affect clinical response include the immune status of the patient, adherence to antifungal therapy, and the potential presence of biofilms formed by Candida organisms[6]. Most patients who experience clinical failure with fluconazole will have Candida species isolates that show in vitro resistance to fluconazole[6,14]. In contrast, patients in whom fluconazole-resistant Candida is isolated will often still respond clinically to fluconazole[15].

Prevention of Fluconazole-Resistant Candidiasis

Preventing fluconazole-resistant candidiasis is best achieved by avoiding unnecessary use of fluconazole or other systemic antifungal agents and by maximizing the patient's immune status with effective antiretroviral therapy[16,17]. In addition, most experts do not recommend chronic maintenance therapy following an episode of oropharyngeal candidiasis, or with recurrent episodes of oropharyngeal candidiasis[16]. Patients with cryptococcal meningitis or recurrent esophageal candidiasis require continuous fluconazole therapy, but systemic antifungal therapy can usually be avoided in patients with less advanced HIV disease and for less serious fungal infections.

Recommended Therapy for Fluconazole-Resistant Candidiasis

The Guidelines for Prevention and Treatment of Opportunistic Infections in Adults and Adolescents provides recommended preferred and alternative treatment options for fluconazole-refractory oropharyngeal and esophageal candidiasis (Figure 5)[3]. These guidelines give the highest rating for itraconazole (Sporanox) oral solution and posaconazole (Noxafil) oral solution. The opportunistic infections guidelines do not provide a specific duration of therapy, but most experts would recommend at least 10 days of therapy for patients with fluconazole-refractory oropharyngeal candidiasis, with extension of the treatment course if the response is not complete at day 10. Patients with esophageal candidiasis should generally receive a minimum of 21 days of therapy. A number of effective intravenous options are effective, including the following intravenous antifungals: deoxycholate amphotericin B (Amphocin, Fungizone), amphotericin B lipid complex (Abelcet), liposomal amphotericin B (AmBisome), micafungin (Mycamine), caspofungin (Cancidas), anidulafungin (Eraxis), and voriconazole (Vfend). In addition, voriconazole is also available in an oral form and it has excellent bioavailability.

Topical Therapy Studies

Available treatment options for fluconazole-refractory oropharyngeal candidiasis include topical therapy, oral systemic agents, and intravenous therapy. Amphotericin B oral suspension is the best-studied topical therapy for fluconazole-resistant candidiasis. In ACTG Study 295, patients with refractory oral candidiasis (after 14 days of treatment with oral fluconazole 200 mg once daily) received amphotericin B oral suspension (100 mg/ml) 5 ml swish and swallow four times daily; 23 (43%) of 54 subjects responded by day 28[18]. Unfortunately, topical amphotericin B is no longer commercially available. Topical therapy with clotrimazole or nystatin has not usually produced good results.

Systemic Therapy Studies

Several reports have described clinical responses to treatment-refractory candidiasis with high-dose fluconazole, but typically resistance will eventually emerge[19]. Several reports have shown good efficacy with itraconazole (Sporanox) oral solution given at a dose of 100 to 200 mg per day in patients with refractory oropharyngeal candidiasis[11,20,21]. The oral solution should be swished in the mouth and then swallowed, as it probably has some topical effect in addition to its systemic effect. In the largest trial involving itraconazole solution, 41 (55%) of 74 patients who failed fluconazole therapy (200 mg once daily) achieved a clinical response by day 28 when treated with itraconazole oral solution (100 mg bid), with 7 days as the median time to response[21]. One study involving 176 HIV-infected patients with fluconazole-refractory oropharyngeal or esophageal candidiasis reported good response rates with oral posaconazole[22]. Studies with voriconazole have shown good in vitro activity against fluconazole-susceptible and fluconazole-resistant strains of Candida[23][21]. Investigators found voriconazole (200 mg PO bid) to be at least as effective as fluconazole in the treatment of esophageal candidiasis, but this study did not involve fluconazole-refractorycandidiasis[24]. Clinicians have used low dose (0.3 mg/kg/day) intravenous amphotericin B for fluconazolerefractory oropharyngeal candidiasis with good success rates[14], but intravenous amphotericin B has significant adverse effects, even when given at a lower dose. Although intravenous liposomal amphotericin B preparations would likely provide good responses, they are significantly more expensive than amphotericin B. In vitro studies with caspofungin have shown excellent activity against fluconazole-resistant isolates[25] and clinical studies have shown good responses with caspofungin in patients with esophagealcandidiasis[26], including fluconazole-refractory cases[27]. Although caspofungin is generally better tolerated than amphotericin B[26], it is very expensive.

References
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1. Powderly WG, Mayer KH, Perfect JR. Diagnosis and treatment of oropharyngeal candidiasis in patients infected with HIV: a critical reassessment. AIDS Res Hum Retroviruses. 1999;15:1405-12 [PubMed Abstract] 2. Barchiesi F, Maracci M, Radi B, Arzeni D, Baldassarri I, Giacometti A, Scalise G. Point prevalence, microbiology and fluconazole susceptibility patterns of yeast isolates colonizing the oral cavities of HIV-infected patients in the era of highly active antiretroviral therapy. J Antimicrob Chemother. 2002;50:999-1002. [PubMed Abstract] 3. Kaplan JE, Benson C, Holmes KK, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association

of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009;58(RR-4):1-207. [CDC and Prevention] 4. Maenza JR, Keruly JC, Moore RD, Chaisson RE, Gallant JE. Risk factors for fluconazole-resistant candidiasis in HIV-infected patients. J Infect Dis 1996;173:219-25. [PubMed Abstract] 5. Maenza JR, Merz WG, Romagnoli MJ, Keruly JC, Moore RD, Gallant JE. Fluconazole-resistant Candida in patients with AIDS: prevalence and microbiology. Clin Infect Dis 1997;24:28-34. [PubMed Abstract] 6. White TC, Marr KA, Bowden RA. Clinical, cellular, and molecular factors that contribute to antifungal drug resistance. Clin Microbiol Rev. 1998;11:382-402. [PubMed Abstract] 7. Martins MD, Lozano-Chiu M, Rex JH. Declining rates of oropharyngeal candidiasis and carriage of Candida albicans associated with trends toward reduced rates of carriage of fluconazole-resistant C. albicans in human immunodeficiency virus-infected patients. Clin Infect Dis. 1998;27:1291-4. [PubMed Abstract] 8. Ghannoum MA, Rice LB. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin Microbiol Rev. 1999;12:501-17. [PubMed Abstract] 9. Martinez M, Lopez-Ribot JL, Kirkpatrick WR, Bachmann SP, Perea S, Ruesga MT, Patterson TF. Heterogeneous mechanisms of azole resistance in Candida albicans clinical isolates from an HIV-infected patient on continuous fluconazole therapy for oropharyngeal candidosis. J Antimicrob Chemother. 2002;49:515-24. [PubMed Abstract] 10. Perea S, Lopez-Ribot JL, Wickes BL, et al. Molecular mechanisms of fluconazole resistance in Candida dubliniensis isolates from human immunodeficiency virus-infected patients with oropharyngeal candidiasis. Antimicrob Agents Chemother. 2002;46:1695-703. [PubMed Abstract] 11. Koks CH, Meenhorst PL, Bult A, Beijnen JH. Itraconazole solution: summary of pharmacokinetic features and review of activity in the treatment of fluconazole-resistant oral candidosis in HIV-infected persons. Pharmacol Res. 2002;46:195201. [PubMed Abstract] 12. Pfaller MA, Boyken LB, Hollis RJ, Kroeger J, Messer SA, Tendolkar S, Diekema DJ. Validation of 24-hour fluconazole MIC readings versus the CLSI 48-hour broth microdilution reference method: results from a global Candida antifungal surveillance program. J Clin Microbiol. 2008;46:3585-90. [PubMed Abstract] 13. Pfaller MA, Diekema DJ, Sheehan DJ. Interpretive breakpoints for fluconazole and Candida revisited: a blueprint for the future of antifungal susceptibility testing. Clin Microbiol Rev. 2006;19:435-7. [PubMed Abstract] 14. Cameron ML, Schell WA, Bruch S, Bartlett JA, Waskin HA, Perfect JR. Correlation of in vitro fluconazole resistance of Candida isolates in relation to therapy and symptoms of individuals seropositive for human immunodeficiency virus type 1. Antimicrob Agents Chemother. 1993;37:2449-53. [PubMed Abstract] 15. Revankar SG, Kirkpatrick WR, McAtee RK, et al. Detection and significance of fluconazole resistance in oropharyngeal candidiasis in human immunodeficiency virus-infected patients. J Infect Dis. 1996;174:821-7. [PubMed Abstract] 16. Powderly WG, Gallant JE, Ghannoum MA, Mayer KH, Navarro EE, Perfect JR. Oropharyngeal candidiasis in patients with HIV: suggested guidelines for therapy. AIDS Res Hum Retroviruses 1999;15:1619-23. [PubMed Abstract] 17. Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America.Clin Infect Dis. 2009;48:503-35. [PubMed Abstract]

18. Fichtenbaum CJ, Zackin R, Rajicic N, Powderly WG, Wheat LJ, Zingman BS. Amphotericin B oral suspension for fluconazole-refractory oral candidiasis in persons with HIV infection. Adult AIDS Clinical Trials Group Study Team 295. AIDS. 2000;14:845-52. [PubMed Abstract] 19. Revankar SG, Dib OP, Kirkpatrick WR, et al. Clinical evaluation and microbiology of oropharyngeal infection due to fluconazole-resistant Candida in human immunodeficiency virus-infected patients. Clin Infect Dis. 1998;26:960-3. [PubMed Abstract] 20. Phillips P, Zemcov J, Mahmood W, Montaner JS, Craib K, Clarke AM. Itraconazole cyclodextrin solution for fluconazolerefractory oropharyngeal candidiasis in AIDS: correlation of clinical response with in vitro susceptibility. AIDS. 1996;10:1369-76. [PubMed Abstract] 21. Saag MS, Fessel WJ, Kaufman CA, et al. Treatment of fluconazole-refractory oropharyngeal candidiasis with itraconazole oral solution in HIV-positive patients. AIDS Res Hum Retroviruses. 1999;15:1413-7. [PubMed Abstract] 22. Skiest DJ, Vazquez JA, Anstead GM, et al. Posaconazole for the treatment of azole-refractory oropharyngeal and esophageal candidiasis in subjects with HIV infection. Clin Infect Dis. 2007;44:607-14. [PubMed Abstract] 23. Ruhnke M, Schmidt-Westhausen A, Trautmann M. In vitro activities of voriconazole (UK-109,496) against fluconazolesusceptible and -resistant Candida albicans isolates from oral cavities of patients with human immunodeficiency virus infection. Antimicrob Agents Chemother. 1997;41:575-7. [PubMed Abstract] 24. Ally R, Schurmann D, Kreisel W, et al. A randomized, double-blind, double-dummy, multicenter trial of voriconazole and fluconazole in the treatment of esophageal candidiasis in immunocompromised patients. Clin Infect Dis. 2001;33:144754. [PubMed Abstract] 25. Pfaller MA, Messer SA, Boyken L, Rice C, Tendolkar S, Hollis RJ, Diekema DJ. Caspofungin activity against clinical isolates of fluconazole-resistant Candida. J Clin Microbiol. 2003;41:5729-31. [PubMed Abstract] 26. Villanueva A, Arathoon EG, Gotuzzo E, Berman RS, DiNubile MJ, Sable CA. A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis. Clin Infect Dis. 2001;33:1529-35. [PubMed Abstract] 27. Kartsonis N, DiNubile MJ, Bartizal K, Hicks PS, Ryan D, Sable CA. Efficacy of caspofungin in the treatment of esophageal candidiasis resistant to fluconazole. J Acquir Immune Defic Syndr. 2002;31:183-7. [PubMed Abstract]

Diagnosis and Management of Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS)

Authors: G. Manoharan, MDChristopher Behrens, MD Clinical Associate Professor University of Washington School of Medicine Departments of Global Health and Medicine Medical Director, International Training & Education Center on Health Disclosure: None

Learning Objectives
A 34-year-old HIV-infected man from southern India is diagnosed with pulmonary tuberculosis (TB) based on symptoms of hemoptysis and weight loss, characteristic findings on chest radiograph (Figure 1), and a sputum smear positive for acid-fast bacilli (AFB). His absolute CD4 count at the time of diagnosis is 60 cells/mm 3, and he has never taken antiretroviral therapy. He is started on anti-TB therapy consisting of isoniazid, rifampin, ethambutol, and pyrazinamide. Two months later, he has a normal chest radiograph (Figure 2) and his sputum is negative on AFB staining. At that time, he begins antiretroviral therapy with a

regimen of zidovudine, lamivudine, and efavirenz. He returns to clinic 2 months later complaining of chest pain and fever; his vital signs are normal. A chest radiograph performed at that time shows a right-sided pleural effusion (Figure 3) with right upper lobe infiltrates (Figure 4). His absolute CD4 count is now 166 cells/mm3. Which of the following would you recommend regarding the management of this patient?

Optimal management at this point consists of administering corticosteroids, continuing TB therapy, and withholdin clinical symptoms improve and his chest radiograph has cleared.

The patient has likely developed multidrug-resistant TB; his TB regimen should empirically be changed and antiret continued.

Given that his CD4 count is still less than 200 cells/mm3, a new opportunistic infection best explains the worsening undergo an intensive evaluation for a new opportunistic infection.

Optimal management at this point consists of continuing antiretroviral medications and TB therapy without change rule out drug-resistant TB, and administering corticosteroids if his clinical condition deteriorates further.

Optimal management at this point consists of continuing antiretroviral medications and TB therapy without change, obtaining sp resistant TB, and administering corticosteroids if his clinical condition deteriorates further.

This answer is correct. This patient's history and chest radiographic findings are most consistent with TB immune reconstitution inflammatory syndrome. Management of this complication typically involves continuing antiretroviral therapy, maintaining the planned course of anti-TB therapy, and adding corticosteroids if needed for moderate or severe disease.

Discussion
Introduction and Overview of TB-IRIS
Immune Reconstitution Inflammatory Syndrome (IRIS) refers to a phenomenon experienced by people living with HIV who have recently initiated antiretroviral therapy. The partial reconstitution of the immune system following initiation of antiretroviral therapy in these patients can result in an exaggerated inflammatory response against any concurrent opportunistic infection. Sometimes the opportunistic infection pathogen against which the inflammatory response is directed remains clinically 'silent' prior to initiation of antiretroviral therapy, such that antiretroviral therapy 'unmasks' a previously undiagnosed disease. Tuberculosis-Immune Reconstitution Inflammatory Syndrome (TB-IRIS) refers specifically to IRIS that occurs in the context of a patient with activeMycobacterium tuberculosis infection, and is a relatively common complication for HIV-infected persons who initiate antiretroviral therapy in resource-limited settings, particularly in regions that have a high TB prevalence. Management of TB-IRIS is complicated by the difficulty in establishing the diagnosis and the absence of randomized controlled trials that clearly define optimal treatment strategies.

Epidemiology
Tuberculosis IRIS is estimated to occur in 11% to 45% of patients co-infected with TB and HIV following initiation of antiretroviraltherapy[1]. Difficulties associated with the diagnosis of TB-IRIS, and the lack (until recently) of a clear case definition for TB-IRIS, have resulted in the wide range of disease estimates. Rates of TB-IRIS within a particular geographic area primarily depend on the prevalence of TB in the region and typical CD4 counts when patients commence antiretroviral therapy. Although TB-IRIS often causes significant clinical symptoms, it is rarely fatal: a recent meta-analysis involving more than 13,000 patients with TB-IRIS reported a case-fatality rate of 3.2%[2]. A case series from South Africa reported a significantly higher mortality rate associated with TB-IRIS among patients in whom TB-IRIS involved the central nervous system[3].

Pathophysiology, Risk Factors, and Clinical Presentation, for TB-IRIS

The exact pathophysiology of TB-IRIS remains unclear, but it appears to result from an invigorated inflammatory reaction againstMycobacterium tuberculosis antigens driven by antiretroviral therapy-induced reconstitution of the immune system[4,5]. Specific risk factors identified for TB-IRIS include multiple prior opportunistic infections, low CD4 count at initiation of antiretroviral therapy, rapid rise in CD4 cell count following initiation of antiretroviral therapy, and a rapid drop in HIV RNA levels following initiation of antiretroviral therapy[4,6,7,8,9]. In addition, persons with more advanced HIV disease at the time of initiation of antiretroviral therapy appear to have increased risk of developing IRIS [10]. Patients with pulmonary TB-IRIS typically present with fever, lymphadenopathy, and respiratory complaints[7]. Given that disseminated disease frequently

develops in HIV-infected persons with active TB, especially in those with advanced HIV infection, TB-IRIS can present in diverse ways. The range of manifestations include abdominal lymphadenopathy, cervical lymphadenitis (Figure 1), abscesses, pulmonary effusions and/or pulmonary infiltrates (Figure 2), pericardial effusions (Figure 3), meningitis, brain tuberculomas, and skeletal lesions (usually vertebral)[11] . In most cases, TB-IRIS typically manifests within 2 months of initiation of antiretroviral therapy [12], though late presentations of TB-IRIS have been reported [13].

Diagnosis and Case Definition of TB-IRIS

The diagnosis of TB-IRIS is rarely straightforward, as no single laboratory test can establish or rule out TB-IRIS. To establish a provisional diagnosis of TB-IRIS, clinicians must rely upon a combination of clinical signs and symptoms, laboratory findings, the likelihood of other conditions, and clinical judgment. In 2008, a panel of expert clinicians convened in Kampala, Uganda to formulate a case definition of TB-IRIS that could be practically applied in resource-limited settings [14]. The International Network for the Study of HIV-associated IRIS panel distinguished between paradoxical TB-IRIS (worsening of previously diagnosed TB disease in a person with HIV infection who initiates antiretroviral therapy) and "unmasking TB-IRIS" (clinical manifestations of previously undiagnosed TB in a person with HIV infection who initiates antiretroviral therapy). This panel also agreed by consensus on a case definition and a provisional case definition for paradoxical TB-IRIS (Figure 4) and unmasking TBIRIS (Figure 5). The case definitions deliberately exclude the use of laboratory tests, such as CD4 and viral load testing, recognizing that clinicians managing HIV-infected persons in resource-limited settings do not routinely have access to such tests. Investigators subsequently validated these case definitions in cohort studies in Thailand [15] and South Africa [16,17], and these definitions remain the most useful case definitions for application in resource-limited settings.

Timing of Antiretroviral Therapy with Known TB

Recently released data from three randomized trials suggest that although delaying the initiation of antiretroviral therapy in patients with HIV and TB coinfection reduces the risk of TB-IRIS, this approach correlates with higher mortality rates when compared with earlier initiation of antiretroviral therapy, especially in patients with low CD4 counts[18,19,20]. The WHO Guidelines therefore recommend starting antiretroviral therapy as soon as tuberculosis therapy is tolerated specifically, as soon as possible (and within 8 weeks) of initiation of anti-TB therapy [21,22].

Use of Corticosteroids in TB-IRIS

Numerous anecdotal reports and small case series have suggested corticosteroids help reduce inflammation in the setting of TBIRIS. Specific formulations and doses used in reports have included intravenous methylprednisolone 40 mg every 12 hours and prednisone 20 to 70 mg per day. The length of steroid administration and the use of a steroid taper have also varied considerably[12]. In the only randomized controlled trial that has evaluated the safety and efficacy of corticosteroids for TB-IRIS, investigators randomized 110 South African HIV-infected persons with evidence of paradoxical TB-IRIS to receive either placebo or a 4-week course of prednisone (1.5 mg/kg/day, for 2 weeks, followed by oral prednisone dosed at 0.75 mg/kg/day for 2 weeks)[23] . The study excluded patients with life-threatening manifestations of TB-IRIS. The primary combined endpoint (days hospitalized plus therapeutic outpatient procedures) was significantly lower in patients randomized to the corticosteroid arm. At weeks two and four of the study, patients who received corticosteroids had higher Karnofsky scores, higher quality of life scores, more frequent improvement in chest radiograph findings, and fewer symptoms, when compared with patients who received placebo (Figure 6 series). Severe infections occurred with equal frequency in the two groups. Corticosteroid therapy was reinitiated in 10 patients after 4 weeks, suggesting that some patients may require an extended course of corticosteroids.

Risk of Drug-Resistant TB in Patients with Suspected TB-IRIS

In a recent cohort study of South African patients, 10% of the patients with suspected TB-IRIS were found to have previously undiagnosed rifampicin-resistant TB[24]. Hence, drug resistance should ideally be ruled out in patients with active TB and a presentation consistent with TB-IRIS, especially if administration of corticosteroids is being considered.

Recommendations for the Management of TB-IRIS

Evidence-based guidelines for the management of suspected or confirmed TB-IRIS in resource-limited setting do not yet exist, owing to the scarcity of randomized controlled trials evaluating management approaches. Nevertheless, we recommend the following general principles of treatment based on existing reports, trials, and expert opinion.

Clinicians should become familiar with the case definitions for TB-IRIS and use these definitions in resource-limited settings. Because no definitive test for TB-IRIS exists, clinicians should consider alternative diagnoses in patients with suspected TB-IRIS, especially if the severity of the condition warrants administering corticosteroids. Clinicians should ideally evaluate the patient for drug-resistant TB, as cases of multidrug-resistant-TB have been identified in patients with TB-IRIS. Most cases of TB-IRIS have a self-limited course and will resolve with continuing treatment with little or no change in overall management. Use of non-steroidal anti-inflammatory agents may provide adequate relief of symptoms in mild cases, though the effectiveness of this approach remains unproven. Patients should continue anti-tuberculous therapy without change unless there is a reason to suspect the current regimen is inadequate (for example if MDR-TB is suspected, or drug-drug interactions could result in suboptimal serum anti-TB drug levels).

In nearly all cases, the patient with TB-IRIS should remain on antiretroviral therapy. Certain circumstances, however, may require temporary interruption of antiretroviral therapy, such as when life-threatening complications of IRIS develop (e.g. increasing intracranial pressure in the setting of TB meningitis, or an expanding abscess that compromises the patients airway). We recommend performing incision and drainage (with stains and cultures) for localized abscesses, though evidencebased guidelines are lacking. Although criteria for initiating corticosteroids remain poorly defined, we recommend administering prednisone for TB-IRIS cases when patients have persistent fever, abscesses, meningitis, or dyspnea. The dosing and duration of corticosteroids should be tailored to individual patient circumstances. We recommend patients with moderate to severe TB-IRIS receive prednisone dosed at 1.5 mg/kg/day for 2 weeks, followed by a taper of 0.75 mg/kg/day over 2 additional weeks. Some patients, particularly those with very high mycobacterial loads or severe clinical deterioration, may require prolonged courses of corticosteroids. The patient receiving corticosteroids for TB-IRIS should undergo careful monitoring for response to corticosteroid therapy. If the patients clinical condition does not improve, the clinician should consider an alternative diagnosis and possible termination of corticosteroids, since administering corticosteroids to a patient with a non-tuberculous opportunistic infection or disease could result in further clinical deterioration. Ideally, the clinician should rule out drugresistant TB before administering corticosteroids.

References
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1. World Health Organization. Workshop on AIDS in Africa: the Bangui Declaration. WHO, 1986. 2. World Health Organization. Case definitions of HIV for surveillance and revised clinical staging and immunological classification of HIV-related disease in adults and children. WHO, 2007. [World Health Organization] 3. World Health Organization. Antiretroviral therapy for HIV infection in adults and adolescents: Recommendations for a public health approach: 2010 revision. WHO, 2010. [World Health Organization] 4. World Health Organization. Antiretroviral therapy for HIV infection in infants and children: Recommendations for a public health approach: 2010 revision. WHO, 2010. [World Health Organization]

5.

6. Figure 1. Cervical Lymphadenitis in Patient with TB-IRIS 7. This image shows a patient with a large cervical lymphatic abscess that developed as a result of TB-IRIS. Source: Professor OC Abraham, Department of Medicine Unit-1 and Infectious Disease unit, Christian Medical College, Vellore, India

8.
9. Figure 2. Chest Radiograph in Patient with Pulmonary Manifestations of TB-IRIS This chest radiograph shows a large right-sided pleural effusion and scattered patchy infiltrates that developed as a result of TBIRIS.

Figure 3. Pericardial Effusion in Patient with and TB-IRIS This chest radiograph shows a patient with TB prior to receiving antiretroviral therapy (Panel A) and the same patient with a large pericardial effusion (Panel B) 2 months after receiving antiretroviral therapy. Source: Government Hospital of Thoracic Medicine, Tambaram Sanatorium, Chennai, India 10. Source: Government Hospital of Thoracic Medicine, Tambaram Sanatorium, Chennai, India

11.
12. Figure 4. INSHI Case Definition for Paradoxical TB-associated IRIS 13. Source: Meintjes G, Lawn SD, Scano F, et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis. 2008;8:51623.

14.
15. Figure 5. INSHI Provisional Case Definition for Unmasking TB-associated IRIS 16. Source: : Meintjes G, Lawn SD, Scano F, et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis. 2008;8:51623.

17.

18. Figure 6: Efficacy and Safety of a Four-week Course of Corticosteroids for HIV-Infected Persons with Paradoxical TB-IRIS in South Africa. Image 1. Study Title and Source

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