Case Study HIV With Diarrhea

7/29/2019 Case Study HIV With Diarrhea

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IV Webstudy

ase HIV with Diarrhea

43-year-old male inmate with stage C3 HIV/AIDS presents with loose, watery stools, abdominal cramping, sweats, fevers,petite (2 months) and 15 lbs weight loss. He is taking Combivir one tablet bid and Nelfinavir 1,000 mg tid, and

methoprim/sulfamethoxazole for secondary pneumocystis carinii pneumonia (PCP) prophylaxis. He reports good adherenc

h an undetectable viral load and a CD4 count of 100 cells/mm3. He was diagnosed with HIV and PCP when he entered the

m Mexico one year ago, at which time he had a CD4 count of 2 cells/mm 3 and "high" HIV-1 viral load. He is an injecting d

er and has sex only with men. He reports unprotected sex with two anonymous partners two to three months ago when he

veled to Mexico. He weighs 130 lbs and is afebrile with normal blood pressure, genital and neurologic exam. His pharynx w

hout thrush; there was no scleral jaundice, some temporal wasting, no rash, abdominal tenderness, organomegaly,

mphadenopathy, or peripheral edema.

What is the differential diagnosis?

Opportunistic pathogens such as disseminated Mycobacterium avium complex (MAC), PCP, andcytomegalovirus (CMV), sh

considered, though PCP does not typically cause GI disease. He is also at risk for Entamoeba histolytica, Dientamoeba fra

stocystis hominis, Giardia lamblia, Campylobacter jejuni, Shigella spp, Salmonella spp, C. difficile, syphilis and herpes sim

us. Because of recent travel to Mexico, Escherichia coli, Vibrio parahaemolyticus, Yersinia spp, rotaviruses, and Norwalk-li

uses are also in the differential. Additionally, this inmate could have diarrhea and wasting from HIV itself. It is not likely th

finavir is causing his diahhrea as he tolerated this drug for nine to ten months and only recently developed diarrhea. Thou

Nelfinavir may not be the cause of the diarrhea, it may be aggravating it.

What tests should you perform/order? Stool samples should be sent for WBCs, to help differentiate inflammatory from non-inflammatory causes of diarrhea (his

watery as opposed to bloody diarrhea suggests non-inflammatory). Stool samples should also be sent for culture for enter

thogens, smear for ova and parasites, Giardia antigen, Clostridium difficile toxins A and B, and acid-fast bacilli (AFB) smeature. Tests for ova and parasites, C. difficile toxins, and smears for AFB should be repeated twice, as it often takes multip

aluations before some of these pathogens are detected. Blood should be sent for AFB culture and routine bacterial culture

re is no temporal association of the onset of diarrhea with antiretroviral therapy and the stool and blood studies are nega

next step in the evaluation is a colonoscopy. The highest yield for colonoscopy is typically in patients with fever, weight l

d a CD4 count of fewer than 200 cells/mm3.

ncentrated exam of the stool showed many cysts of Giardia lamblia and Entamoeba histolytica. This diagnosis should be

ported to the local public health department. Many Entamoeba coli cysts, manyEndolimax nana cysts, and moderate Iodam

tschlii cysts were also seen. On auramine stain, moderate cryptosporidia were detected.

What treatment(s) should you offer this inmate? Are there drug-drug interactions to consider?

Endolimax nana, Entamoeba coli , and Iodamoeba butschlii are nonpathogenic commensals and as such require no treatm

ey are however markers of exposure to human feces and are often found in patients who are also infected with pathogeni

anisms. Giardia and Entamoeba histolyticacan cause invasive disease and should generally be treated. The drug of choice

rdiasis is metronidazole 250 mg tid for seven days, which also has activity against E. histolytica. Unfortunately, there are

able therapies for Cryptosporidiosis, though paromomycin or nitazoxanide may have activity and offer benefit. Supportive

h hydration and nutrition, as well as institution of an effective antiretroviral regimen, are crucial aspects of care since

provement in the immune system often helps eradicate the infection. In immunocompetent hosts, cryptosporidiosis is usu

f-limited. It may be in this inmate's best interest to change his medications to a more potent antiretroviral regimen in an

mprove his T-cell response and minimize his gastrointestinal side effects. If the regimen is not changed, the dose of Nelfi

ould be changed to 1,250 mg po bid as this dose is easier to take and is associated with fewer loose stools compared to th

se. There are no known drug-drug interactions between metronidazole, paromomycin, or nitazoxanide and the antiretrovir

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is currently taking. There is a drug-drug interaction between the oral solution form of the protease inhibitor amprenavir a

tronidazole. This is not true for the capsule formulation of amprenavir.

What infection-control measures should you recommend?

To minimize secondary transmission to others via fecal-oral spread, it is important to educate the inmate and staff on goo

nd-washing skills, particularly before and after meals and use of the restroom. He should be excluded from any kitchen wo

til his diarrhea has resolved and his stool is cleared of all organisms.

thany Weaver, D.O., M.P.H., is Acting Instructor of Medicine at the University of Washington Center for AIDS & STD Resea

FAR) and Northwest Correctional Medicine Education Program. Disclosures: Stockholder, Pfizer.

eferences

. Amadi B, Mwiya M, Musuku J, Watuka A, Sianongo S, Ayoub A, Kelly P. Effect of nitazoxanide on morbidity and mortali

Zambian children with cryptosporidiosis: a randomised controlled trial.Lancet . 2002 Nov 2;360(9343):1375-80.

. Connolly GM, Foirbes A, Gazzard BG. Investigation of seemingly pathogen-negative diarrhea in patients infected with H

1. Gut 1990;31:886-89.

. DeHovitz JA, Pape JW, Boncy M, Johnson WD Jr. Clinical manifestations and therapy of Isospora belli infection in patienwith the acquired immunodeficiency syndrome. N Engl J Med . 1986;315:87-90.

. Guerrant RL, Bobak DA. Bacterial and protozoal gastroenteritis. N Engl J Med 1991;325:327-40.

. 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.

. Kotler DP, Francisco A, Clayton F, et al. Small intestinal injury and parasitic diseases in AIDS. Ann Intern Med .

1990;113:444-49.

. Laughon BE, Druckman DA, Vernon A, et al. Prevalence of enteric pathogens in homosexual men with and without acq

immunodeficiency syndrome. Gastroenterology . 1988;94:984.

. Oldfield EC III. Evaluation of chronic diarrhea in patients with human immunodeficiency virus infection. Rev Gastroente

Disord . 2002 Fall;2(4):176-88. Review.

. 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.

0. 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.

1. Rossignol JF, Hidalgo H, Feregrino M, Higuera F, Gomez WH, Romero JL, Padierna J, Geyne A, Ayers MS. A double-'blin

placebo-controlled study of nitazoxanide in the treatment of cryptosporidial diarrhea in AIDS patients in Mexico. Trans

Soc Trop Med Hyg. 1998 Nov-Dec;92(6):663-6.

2. Parasites and Parasitologic Resources of the Ohio State University www.biosci.ohio-state.edu/~parasite/.

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

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

earning Objectives

1-year-old HIV-infected woman presents with severe diarrhea and dizziness. She has long-standing HIV disease and her ent CD4 count was 24 cells/mm3. For approximately 2 years, she has not taken any medications related to her HIV disease diarrhea began about 10 days ago and now she is having 10 to 15 watery stools per day, abdominal cramping, and nausysical examination shows a thin female with a temperature of 38.1°C, blood pressure of 86/60 mmHg, and minimal diffusedominal tenderness with deep palpation. A modified acid-fast stain on a stool sample is presumptively identifiedCryptosporidium species (Figure 1).

hich of the following is TRUE regarding diarrheal illness caused by Cryptosporidium in HIV-infected patients?

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http://www.biosci.ohio-state.edu/~parasite/



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Most patients acquire Cryptosporidium from exposure to undercooked meat.

Among antimicrobial agents studied for the treatment of cryptosporidiosis, the combination of azithromyci

( 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 cryptosporid

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

iscussion- Cryptosporidiosis

ckground and Epidemiologyyptosporidium species are intracellular, spore-forming protozoan parasites that infect the epithelium of thestrointestinaltract[1,2,3]. Ten species of Cryptosporidium exist, with most human infections caused by C. parvum and lesquently by C. hominis and C. meleagridis[1,2]. Infection with Cryptosporidium in immunocompetent persons often resultsymptomatic or mild self-limited disease, but in HIV-infected patients, particularly those with low CD4 counts, infection mayult in chronic or life-threatening diarrhea, or extra-intestinal disease[1,2,4,5,6]. In developed countries, an estimated 14

DS patients with diarrhea have Cryptosporidium infection[1]. Before the widespread use of HAART, Cryptosporidium oocys

ores) were detected in up to 4% of HIV-infected patients in the United States[5]. More recently, infection rates in developuntries have decreased dramatically, with a contemporary incidence of cryptosporidiosis amongst AIDS patients estimateds than 1 per 100person-years[2].

e Cycle and Transmissionman infection occurs with ingestion of viable Cryptosporidium oocysts. After the oocysts are ingested, they release sporozich then invade epithelial cells in the gastrointestinal tract, primarily in the small intestine (Figure 1)[1]. After entry into thelial cells, the sporozoites mature into trophozoites, which then reproduce in two cycles. In the asexual cycle the organdergoes asexual reproduction (schizony), producing merozoites (type I), which are emitted into the lumen of the intestineect other gastrointestinal epithelial cells, thus multiplying and locally increasing the organism burden[3]. In the sexual cycme of the merozoites (type II) attach to epithelial cells, mature into gametocytes, which are fertilized in the intestinal tracn form into oocysts. The oocysts then release sporozoites that can either reinfect the intestinal epithelium and start the li

cle anew or be shed in feces, capable of infecting others[1]. The Cryptosporidium oocysts passed via feces may subsequentransmitted by human-to-human or human-to-animal contact, or by consumption of contaminated drinking water [2,7].

rson-to-person transmission requires ingestion of as few as 10 to 100 oocysts, with transmission rates as high as 19% amusehold contacts of individuals with acute cryptosporidiosis[3]. Cattle and sheep are common animal reservoirs of parasite[1].

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

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nical Manifestationser an incubation period of 7 to 10 days, infection of the gastrointestinal tract by Cryptosporidium impairs absorption andhances secretion, typically leading to watery, non-bloody diarrhea[1]. The duration and severity of disease depend on themune response, ranging from an asymptomatic or mild self-limited illness, to chronic low-level diarrhea, to a profuse choleeillness[1,5]. Patients with a strong Cryptosporidium serologic response and previous exposure(s) are more likely to haveymptomatic infection, though they may still shed oocysts in feces and be contagious[5]. Patients' CD4 cell counts are a stdictor of whether they will develop self-limited or persistent disease. In a retrospective analysis, HIV-infected patients witf-limited cryptosporidiosis had a mean CD4 count of 312 cells/mm3 compared to those with persistent infection, who had an CD4 count of 57 cells/mm3 (Figure 2)[4]. This same report found that 87% of patients with a CD4 count less than 14s/mm3 who had cryptosporidiosis developed persistent disease. Patients with fulminant infection typically have a CD4 cou

s than 50 cells/mm3, and these patients rarely completely clear the infection, presumably because the organism can use tary tree as areservoir[1]. Fever occurs in up to one-third of patients, and abdominal cramping, nausea, weight loss, andlabsorption arecommon[1,2].

tra-Intestinal Manifestationsients with advanced immunosuppression also have an increased risk for developing extra-intestinal disease, which usually

curs within the biliary tract, but case reports have documented infection in the lungs, stomach, pancreas, and middle ear[en Cryptosporidium invades the epithelial cells of the biliary tract, the result may mimic primary sclerosing cholangitis, oracalculous cholecystitis or papillary stenosis, which can cause pancreatitis[2,7]. Studies have revealed Cryptosporidium ast commonly identified pathogen in cases of AIDS-related cholangiopathy[7]. Clinicians should consider this clinical entityy HIV-infected patient presenting with fever, right upper quadrant abdominal pain, nausea, and vomiting.

agnosis

gnostic testing for Cryptosporidium should be performed in HIV-infected patients who develop acute diarrhea, chronic diabiliary tract disease, especially if their CD4 count is less than 200 cells/mm3. The easiest way to confirm the diagnosis is tntify oocysts with microscopic examination of stool or tissue. Routine ova and parasite testing doest detect Cryptosporidium.The[1] modified acid-fast stain, which stains the organism red, is the most common method usetect Cryptosporidium on stool microscopic examination (Figure 3)[1,2]. Cryptosporidium can be differentiated from yeastich are similar size and shape but are not acid fast[2], and from other protozoan parasites, such as Cystoisospora (Isospoli and Cyclospora species, based on size (Figure 4)[3]. Patients with mild disease may require repeat stool testing due toh false negative rates with low organism burden[2]. If modified acid fast staining is negative and clinical suspicion is highect immunofluorescence microscopy (Figure 5) and ELISA testing of stool have greater sensitivity and specificity[1,2].rologic testing of blood generally does not help in making the diagnosis, mainly because exposure to Cryptosporidium ismmon and healthy persons who do not have active disease may test positive[2]. Endoscopy is often normal, but patients vere disease may have reduction of duodenal folds secondary to villous atrophy[7]. Hematoxylin and eosin stains or lightcroscopy may be performed from mucosal biopsies (Figure 6)[7] .If a patient demonstrates symptoms of biliary tract disultrasound is often the first test of choice, but endoscopic retrograde cholangiopancreatography (ERCP) is more sensitive

eneral Approach to Treatmentients who are asymptomatic or have intact immune function generally do not require treatment for cryptosporidiosis. Themary treatment for AIDS patients with symptomatic cryptosporidiosis is to restore immune function with effective antiretrrapy (Figure 7 and Figure 8)[1,6,7]. Cell-mediated immunity is vital for protection against cryptosporidiosis, and in ma

ses, an increase in CD4 count to greater than 100 cells/mm3 may result in resolution of symptoms[2]. Patientsh Cryptosporidiuminfection and CD4 cell counts greater than 350 likely will have a self-limited illness, but may benefit frotimicrobial therapy. Several antimicrobial agents have been studied for the treatment of cryptosporidiosis in HIV-infectedtients, including nitazoxanide ( Alinia), paromomycin (Humatin), and azithromycin (Zithromax ). No antimicrobial agent,wever, has been shown to be reliably effective against Cryptosporidium in the absence of antiretroviral therapy. Whentimicrobial therapy is used in combination with antiretroviral therapy, nitazoxanide is the recommended agent[2]. Sincetients with severe cryptosporidiosis typically have clinically-significant dehydration, supportive care with fluid rehydration actrolyte repletion is an important component of therapy. Antimicrobial therapy has not been reliably effective against AIDolangiopathy, so if biliary disease is present, endoscopic therapy may be necessary. Specific interventions consist of

hincterotomy for papillary stenosis (which relieves cholangitis and may relieve pain, but does not improve survival), orolecystectomy for cholecystitis (which does not clear the organism, indicating there may be a hepatic reservoir)[7].

timicrobial Agentstazoxanide: The antimicrobial nitazoxanide is typically well tolerated with minimal drug interactions, and although good dst for its effectiveness in immunocompetent patients with cryptosporidiosis, data in the HIV-infected population are mixedmpassionate use study in 2006 that used nitazoxanide 500 to 1500 mg twice daily in 365 AIDS patients for median 62 day% of subjects had a sustained clinical response (sustained improvement in the patient's global assessment of strointestinal symptoms)[9]. A double-blind, placebo-controlled study of nitazoxanide in patients with AIDS randomizedrticipants to nitazoxanide 500 mg twice daily, 1000 mg twice daily, or placebo for 14 days; the patients then crossed overferent group based on random assignment. Participants who received the drug at either dose had higher rates of parasitedication from stool samples than patients treated with placebo, and 19 of 22 patients whose stool was cleared of the para

perienced resolution of their diarrheal symptoms (Figure 9)[10]. In contrast, a 2007 systematic review and analysis of
































































































































ptosporidiosis treatment in HIV-infected patients found that nitazoxanide without antiretroviral therapy provided minimalnefit in controlling diarrhea or in reducing oocyst clearance when compared with placebo[6]. Therefore, nitazoxanide mayed for the treatment of cryptosporidiosis, but it is not a substitute for effective antiretroviral therapy[2].

romomycin: Although paromomycin is not FDA-approved for the treatment of cryptosporidiosis, data from animal modelggest high-dose paromomycin has significant activity against Cryptosporidium[2]. In addition, studies have demonstratedponse rates to be as high as 67% in humans, but frequent relapses cause long-term response rates to be as low as 33%ccess rates are even lower in patients with CD4 counts less than 100 cells/mm3[2]. In one randomized controlled trial thampared paromomycin 500 mg four times daily for 21 days with placebo in 35 HIV-infected adults with a CD4 count less thual to 150 cells/mm3 (median 24 cells/mm3), response rates between the paromomycin and placebo arms did not show a

tistically significant difference; the investigators concluded that paromomycin monotherapy was ineffective (Figure 10)[1erefore, paromomycin is not recommended as monotherapy for cryptosporidiosis[2].

ithromycin: In a small study, 13 HIV-infected patients with symptomatic cryptosporidiosis received azithromycin therapyses ranging from 500 to 1500 once daily for 20 to 50 days [12]. Nine of the 13 patients had a good clinical and parasitologponse. A trial from India examined the efficacy of azithromycin (500 mg for 5 to 14 days) in 41 HIV-infected patientsh Cryptosporidium infection[13]. Most of these patients, however, had asymptomaticCryptosporidium infection. Among th

mptomatic patients, all had symptomatic improvement (50% reduction in baseline stool frequency with a feeling of well-beer 5 days of azithromycin 500 mg once daily, but only 5 of the patients had clearance of Cryptosporidium oocysts from st

romomycin plus Azithromycin: A small study involving 14 patients with a CD4 counts less than or equal to 100s/mm3 (median 30 cells/mm3) demonstrated reduced oocyst excretion and some clinical improvement with a 28-day cour

romomycin 1g twice daily plus azithromycin 600 mg once daily followed by paromomycin alone x 12weeks[14].

mmary Treatment Recommendations

The primary and preferred therapy for symptomatic cryptosporidiosis in HIV-infected patients with advancedimmunosuppression 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 withantiretroviral 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 losbut are not effective treatment.

For patients with cryptosporidiosis-related biliary disease, expert consultation is recommended

eferences

arch: Start typing to begin a search

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-infadults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Associaof 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, cyclospor

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. AIntern 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 strongserological response to a Cryptosporidium-specific antigen group, in HIV-infected individuals. J Infect Dis. 2005;19221.[PubMed Abstract]






























http://www.ncbi.nlm.nih.gov/pubmed/12037153
































6. Abubakar I, Aliyu SH, Arumugam C, Usman NK, Hunter PR. Treatment of cryptosporidiosis in immunocompromisedindividuals: 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;22:27[PubMed Abstract]

8. Inungu JN, Morse AA, Gordon C. Risk factors, seasonality, and trends of cryptosporidiosis among patients infected whuman 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: resuthe 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 treatmentcryptosporidial 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 IDis. 2000;31:1084-92.[PubMed Abstract]

12. Dionisio D, Orsi A, Sterrantino G, et al. Chronic cryptosporidiosis in patients with AIDS: stable remission and possibleeradication 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 humanimmunodeficiency 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 InDis. 1998;178:900-3.[PubMed Abstract]







































is figure is from Chen XM, Keithly JS, Paya CV, LaRusso NF. Cryptosporidiosis. N Engl J Med. 2002; 346:1723

produced with permission from the Massachusetts Medical Society. Copyright © 2002 Massachusetts Medical

ciety. All rights reserved.



odified Acid-fast Staining of Stool Samples Showing Cryptosporidium Oocysts



dated April 3, 2008

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

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

earning Objectives

27-year-old man from Mexico with newly diagnosed HIV (CD4 count 7 cells/mm 3 and HIV RNA greater than 1 million copiesents to the clinic with 4 weeks of fever, chills, night sweats, myalgias, dry cough, nausea, vomiting, and diarrhea. He hatery bowel movements 1-2 hours after eating, and has lost 25 lbs in the last 4 weeks. He recently had a negative tubercun test. Initial evaluation shows hypoxia evident on an arterial blood gas and a chest radiograph with diffuse hazy opacitiesgure 1). He is initially treated for presumptive Pneumocystis pneumonia and atypical pneumonia. Two weeks later, howegal blood cultures show growth of hyphal elements identified as Histoplasma capsulatum and thus he is diagnosed with

ogressive disseminated histoplasmosis.

hich of the following is True about this patient’s treatment?

e preferred initial therapy for HIV-infected patients with progressive severe disseminated histoplasmosis is itraconazole (S

he patient does not tolerate itraconazole for maintenance therapy, fluconazole (Diflucan) can be used and expected to ha

apse.

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

ring maintenance therapy, obtaining Histoplasma antigen levels is not recommended because they have no value in monit

u answered:






















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

s answer is correct. Monitoring serum itraconazole levels during maintenance therapy is recommended, and although rients should generally have a random serum itraconazole level of at least 1.0 μg/mL. Achieving serum itraconazole levelsds to greater toxicity.

gure 1. Chest Radiograph of AIDS Patient with Disseminated Histoplasmosis

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

scussion - Disseminated Histoplasmosis

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

thogenesis and Risk Factorstoplasmosis occurs in humans when microconidia are inhaled and transformed into yeast in the lungs[1]. Clinical disease ctivation of prior infection[5]. The risk and severity of illness depend on the number of conidia inhaled and the cellular imreases dramatically with CD4 count less than 50 cell/mm3[6], and 90% of cases occur with a CD4 count less than 200 celcrophages, which facilitatesdissemination[1]. Macrophages from HIV-infected patients, especially those with low CD4 cell

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

nical Manifestationstoplasma infection can be asymptomatic or symptomatic, acute or chronic, and focal or disseminated[8]. Immunocompetalized to the lungs. In HIV-infected patients, disseminated disease often develops, particularly in those who have a CD4 comple, in one outbreak in Indianapolis, 95% of patients with AIDS who developed histoplasmosis developed disseminated

V-infected patients from 1990 to 1993 in Kansas City, 74% of patients with histoplasmosis had symptomatic disease, and seminated disease[5]. Untreated disseminated disease usually progresses in an indolent manner over 1 to 3 months, but ically present with nonspecific symptoms such as fever, fatigue, anorexia, and weight loss[2]. Approximately 50% of case

iography often shows diffuse or patchy opacities that can mimic Pneumocystis pneumonia, as in the case presented. Lesstrates, nodules, or cavities. Patients may also have hepatosplenomegaly (25%), lymphadenopathy (25%), sepsis (10 to 2to 20%), or gastrointestinal involvement (10 to 20%)[1]. Central nervous system involvement portends a poor prognosi

mphocytic meningitis. Disease can occur anywhere along the gastrointestinal tract and may cause diarrhea, abdominal painnifestations are present in about 10% of patients and can be papular, maculopapular or pustular in nature, or can occur inltiforme, eczematous rash, or rosacea-like rash[1]. Mucosal lesions occur more often with disseminated histoplasmosis thude superficial ulcerations, deep ulcerations, nodular masses or verrucous lesions of the lips, tongue, gingival pharynx or

ect the adrenal glands than other endemic mycoses, leading to adrenal insufficiency in a number of cases[2]. Common labtoplasmosis include anemia, leucopenia, thrombocytopenia, elevated alkaline phosphatase, elevated erythrocyte sedimenttate dehydrogenase (LDH)[2].

agnosissible diagnostic methods for histoplasmosis include culture, fungal stains (of body fluids or tissues), serologic testing, and

ients, the sensitivity of serologic tests ranges from 85 to 100%, depending on the type of Histoplasma infection. Immunoctoplasmosis, however, often do not mount a robust antibody response and thus have high false-negative rates with seroloseminated disease with a large fungal load, culture and antigen detection are generally preferred in this setting[10]. The seminated histoplasmosis in AIDS patients is approximately 85% (Figure 1)[1]. In a study that examined antigen testingtoplasmosis during a 5-year period in Indianapolis, antigen testing of urine had the highest yield (95%), followed by serumnchoalveolar lavage fluid (70%) (Figure 2)[1]. For patients with localized pulmonary disease, antigen testing has poor seseminated disease, it remains the most sensitive test available[3,10]. Antigen detection has a specificity greater than 98%mpared with culture, which typically takes 2 to 4 weeks to turn positive)[1]. Antigen cross-reactivity can occur with cocciacoccidioidomycosis, but often these can be differentiated by history and epidemiology. In some patients with disseminatw yeasts present withinneutrophils[2]. Skin biopsy can provide the fastest diagnosis in patients who have skin disease. Irrow biopsy can be useful and may give a diagnosis more rapidly than antigen testing. Overall, given the significant false-thod, most experts recommend sending a combination of tests.

dications for Treatment

e indications for treatment are summarized in the Clinical Practice Guidelines for the Management of Patients with Histoplaeases Society of America (IDSA) (Figure 3)[11]. Treatment for histoplasmosis is not generally indicated in mild disease tove, however, most HIV-infected patients suffer from disseminated disease, and treatment in these cases is always indicahout treatment, progressive disseminated histoplasmosis is usually fatal[2]. Treatment is also indicated (with good evidenonic pulmonary, and central nervous system disease. Though treatment recommendations exist for mild acute pulmonaryere and persistent mediastinal lymphadenitis, and symptomatic mediastinal granuloma, evidence for these recommendat

SA guidelines and have not been definitively proven[11].

eatment for Disseminated and Central Nervous System Diseaseatment regimens for histoplasmosis vary depending on the type and severity of disease. The following treatment recomm

SA guidelines for the management of patients with histoplasmosis; these recommendations are not specific to persons witderate to severe progressive disseminated infection, the recommended therapy consists of liposomal amphotericin B ( Amconazole (Sporanox ) for at least 12 months. The itraconazole capsules or solution may be used, but the capsules should beceptor blocker or a proton pump inhibitor. Use of amphotericin B lipid complex ( Abelcet ) may be preferred in some patieaddition, deoxycholate amphotericin B is considered a less expensive possible alternative to lipid formulations of amphote-risk for nephrotoxicity[11].

e preference for liposomal amphotericin B is based on a 2002 study involving AIDS patients with moderately severe to sevsomal amphotericin B was associated with greater efficacy and less toxicity than amphotericin B deoxycholate (Figure 5)ial therapy for patients with moderate to severe disseminated disease based on data that deoxycholate amphotericin B leatures than itraconazole (85% versus 53% at 2 weeks), more robust decline in serum antigen levels (1.6 versus 0.1 units els (2.1 versus 0.2 units at 2 weeks)[12]. For patients with mild to moderate progressive disseminated histoplasmosis, itrecommended [11]. Patients with central nervous system histoplasmosis should receive high-dose liposomal amphotericinconazole for at least 12 months.

eatment for Pulmonary Disease







































































































e first-line recommendation for moderate to severe acute pulmonary histoplasmosis is intravenous liposomal amphotericinl itraconazole for 12 weeks. A 1 to 2 week course of intravenous methylprednisolone is recommended for patients who deere hypoxemia[11]. If disease is mild but persists for longer than 4 weeks, itraconazole is effective (6 to 12 weeks of theseminated). The recommendations for treatment of patients with histoplasmosis manifesting as chronic cavitary pulmonardules, mediastinal disease, pericarditis, or rheumatologic disease are not discussed here but are provided in detail in the 2

ernative Antifungal Agents for Treatment of Histoplasmosisconazole (Diflucan) has been used to treat histoplasmosis, but studies have shown high rates of relapse and developmenten other therapies fail. Ketoconazole (Nizoral ) is not generally used because of higher rates of side effects compared with ole" drugs, posaconazole (Noxafil ) and voriconazole (Vfend ) both show in vitro activity against histoplasma; a 2006 study

conazole induces cross-resistance to voriconazole[14]. small case series including six patients with severe histoplasmosis mising results using posaconazole for salvage therapy, but more studies with this drug are needed[15]. Therefore, fluconiconazole are all considered as second-line agents forhistoplasmosis[11]. Echinocandins are not recommended for the tre

onitoring Patients on Therapycause serum levels of itraconazole vary significantly based on absorption, the formulation used (levels are generally higheg interactions, levels should be checked 2 weeks after initiation of therapy or any dose change. Checking levels can also hatment failure. The exact target level has not been defined, but according to the 2007 IDSA guidelines, it is generally recoum itraconazole level of at least 1.0 mcg/mL to prevent treatment failure. Levels greater than 10 mcg/mL are unnecessarum itraconazole levels do not vary significantly throughout a 24-hour period, the timing of the blood draw in relation to thportant and thus random levels are acceptable[11].

toplasma antigen levels can be used to follow the effect of treatment and monitor for relapse. Both serum and urine

igen concentrations decrease throughout the course of therapy, eventually to undetectable levels, although this may take

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

scontinuing Maintenance Therapyditionally,it was thought that lifelong maintenance therapy was required for all AIDS patients with histoplasmosis to prevet patients with AIDS who have a sustained immunologic response to antiretroviral therapy may safely discontinue histopla

04 followed 32 patients after at least 12 months of antifungal therapy for histoplasmosis and at least 6 months of HAART [

ease and CD4 counts greater than 150 cells/mm3. There were no relapses after two years of follow-up[16]. Therefore, theients with disseminated histoplasmosis who are on HAART can safely discontinue itraconazole therapy if the following coneast 12 months of itraconazole therapy, (2) fungal blood cultures are negative, (3) serum and urine antigen levels are lesays), and (4) CD4 count is greater than 150 cells/mm3. Nevertheless, patients require lifelong suppressive therapy with it

apse (which occurs in 10-15% of cases), fail HAART, or if their CD4 count decreases to less than 150 cells/mm3[11]. The ctice of discontinuing therapy is common, the evidence behind it is limited.

le of Initiating Antiretroviral Therapyrting HAART in patients with disseminated histoplasmosis is important because it is associated with better responses to ah histoplasmosis who were taking HAART had much better response rates to antifungal therapy (95.5% versus 47.4%) anumented cases of immune reconstitution inflammatory syndrome (IRIS) in patients with histoplasmosis, but it is rare andayed for that reason[11]. Drug-drug interactions are an important consideration when starting HAART in a patient on antig-drug interaction may occur between itraconazole and efavirenz (Sustiva, also contained in Atripla). In one case report, els, and the patient developed an increase in urine histoplasma antigen levels. Increasing the dose of itraconazole did nottoplasma antigen levels only decreased after the patient switched to a protease-inhibitor based antiretroviral regimen[17opinavir-ritonavir (Kaletra) or atazanavir (Reyataz ) plus ritonavir (Norvir ) can have the opposite effect, causing increased

eferences


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 adolesceNational Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. MMWR Recom[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 imand pathophysiology. Clin Infect Dis. 1997;24:1195-203.[PubMed Abstract]

6. Tobón AM, Agudelo CA, Rosero DS, et al. Disseminated histoplasmosis: a comparative study between patients with ahuman 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 defectivcapsulatum. J Infect Dis. 1995;171:320-7.[PubMed Abstract]

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

9. Wheat LJ, Chetchotisakd P, Williams B, Connolly P, Shutt K, Hajjeh R. Factors associated with severe manifestations 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 management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect[PubMed Abstract]

12. Wheat LJ, Cloud G, Johnson PC, Haddad N, Le Monte A, Brizendine E, Hafner R. Clearance of fungal burden during treliposomal 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 amhistoplasmosis 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 wChemother. 2006;57:1235-9.[PubMed Abstract]

15. Restrepo A, Tobon A, Clark B, et al. Salvage treatment of histoplasmosis with posaconazole. J Infect. 2007;54:319-2[PubMed Abstract]

16. Goldman M, Zackin R, Fichtenbaum CJ, et al. Safety of discontinuation of maintenance therapy for disseminated histoantiretroviral therapy. Clin Infect Dis. 2004;38:1485–9.[PubMed Abstract]

17. Koo HL, Hamill RJ, Andrade RA. Drug-drug interaction between itraconazole and efavirenz in a patient with AIDS and2007;45(6):e77-9.[PubMed Abstract]

18. Crommentuyn KM, Mulder JW, Sparidans RW, Huitema ADR, Schellens JHM, Beijnen JH. Drug-drug interaction betwelopinavir/ritonavir in an HIV1–infected patient with disseminated histoplasmosis. Clin Infect Dis. 2004;38:e73–5.[PubMed Abstract]

gure 1. Estimated Sensitivities of Diagnostic Tests for Disseminated Histoplasmosis in Patients wit




http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5315a1.htm



































































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

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

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

s graph shows a comparison of different Histoplasma antigen tests for the diagnosis of histoplasmosis in patietoplasmosis. In this figure, n represents the number of patients tested.

apted from: Wheat J. Endemic mycoses in AIDS: a clinical review. Clin Microbiol Rev. 1995;8:146-59. Wheaview. Clin Microbiol Rev. 1995;8:146-59.

gure 3. Indications for Antifungal Treatment for Different Manifestations of Histoplasmosis



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

apted from: Wheat LJ, Freifeld AG, Kleiman MB, Baddley JW, McKinsey DS, Loyd JE, Kauffman CA; Infectious actice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases07;45:807-25.

gure 4. Recommendations for the Treatment of Severe Manifestations of Histoplasmosis



gure 5. Comparison of Liposomal Amphotericin B and Conventional Amphotericin B for Induction Therapy of H



s randomized, double-blinded trial involved 81 patients with AIDS and moderate to severe disseminated histo1 ratio to receive intravenous liposomal amphotericin B ( AmBisome) 3 mg/kg/d or conventional amphotericin tient who had successful induction therapy, then received itraconazole for 10 weeks as consolidation therapy. eived liposomal amphotericin B had higher clinical efficacy of induction therapy (P = 0.014) and less nephroto

ose who received conventional amphotericin B.

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

ase 4: Fluconazole-Resistant Oropharyngeal Candidiasis

thor: David H. Spach, MD

arning Objectives

3-year-old HIV-infected woman presents to the clinic with oral candidiasis that is clinically not responding to fluconazole (vanced immune suppression with a CD4 count of 22 cells/mm3 and HIV RNA of 46,340 copies/ml. She is taking a 5-drug smethoprim-sulfamethoxazole (Bactrim, Septra), azithromycin (Zithromax ), and fluconazole. She has taken fluconazole on pharyngeal candidiasis and the past 3 months she had taken fluconazole 200 mg PO once daily. She currently denies any

hich 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 candi

sulfamethoxazole for longer than 60 days.

Fluconazole exerts its effect by inhibiting fungal cell wall synthesis. Fluconazole resistance in Candida spec

increase production in cell wall precursors.

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More than 95% of Candida albicans isolates from patients with fluconazole-refractory oropharyngeal candi

(Sporanox ). Fewer than 5% of patients with fluconazole-refractory oropharyngeal candidiasis will respond

200 mg per day.

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

Ans

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

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

ase 4: Discussion

idemiology and Risk Factorsring the 1980s and 1990s, numerous reports emerged describing the development of refractory oropharyngeal candidiasisDS patients following prolonged exposure to fluconazole (Diflucan)[1]. The emergence of fluconazole-resistant candidiasisV-infected persons correlated with the widespread use of fluconazole for oropharyngeal candidiasis during this time periodring the 1980s and 1990s, the percentage of fluconazole-resistant Candida species ranged from approximately 5 to 33%[addition, following the widespread use of fluconazole, the proportion of C. albicans isolates decreased ander Candida species, including C. krusei , C. dubliniensis, and C. glabrata, increased. Fluconazole-resistant oropharyngeal

ndidiasis has involved both C. albicans and the non-albicans species. From a clinical standpoint, treatment-refractoryndidiasis is defined as signs and symptoms of candidiasis that persist for longer than 7 to 14 days after appropriate therapvestigators have identified low CD4 cell count, advanced immunosuppression, greater number of fluconazole-treated episod longer median duration of fluconazole therapy as the most important risk factors [3,4,5,6]. In more recent years, clinicive observed a major decrease in the frequency of fluconazole-resistant oropharyngeal candidiasis, predominantly as a res widespread use of potent combination antiretroviral therapy[7]. Nevertheless, treatment refractory oropharyngeal candil occurs in approximately 5% of HIV-infected persons[3].

echanisms for Fluconazole Resistanceosterol is the predominant sterol in the fungal membrane and it serves as a bioregulator of fungal membrane fluidity

dintegrity[8]. The synthesis of ergosterol requires multiple steps and multiple enzymes (Figure 1). Fluconazole exerts itsion on the fungal membrane by inhibiting the fungal cytochrome P-450 enzyme 14 alpha-demethylase, thereby blocking t

nversion of lanosterol to ergosterol (Figure 2)[6]. The inhibitory action of fluconazole causes depletion of ergosterol whicn alters the fungal membrane structure and function. The inhibition of 14 alpha-demethylase also results in the build-up oosterol and other ergosterol precursors. The alterations in the fungal cell membrane eventually lead to fungal cell death. Tective action of fluconazole for fungal cell membranes occurs because human cells use cholesterol, not ergosterol, for thenthesis of cell membranes. The echinocandins have a mechanism of action distinct from the azoles: these agents inhibit fu wall synthesis by blocking the production of 1,3-beta-D-glucan. Resistance to fluconazole can develop as a result of an

eration in the target enzyme 14 alpha-demethylase (change in binding site or over expression of the enzyme) (Figure 3)m enhanced drug efflux caused by plasma membrane transporters (Figure 4)[6,7,9,10,11]. Many of the strains of

conazole-resistant Candida species display multiple mechanisms of resistance[7].

efinition of Fluconazole Resistance2008, the Subcommittee for Antifungal Testing of the Clinical Laboratory Standards Institute (CLSI) defined breakpoints fotifungal agents active against Candida species. Isolates with a fluconazole MIC less than 8 mcg/ml are classified as sensiti, those with 16 to 32 mcg/ml as dose-dependent sensitive (S-DD), and those with greater than or equal to 64 mcg/ml areistant[12,13]. Primary fluconazole resistance is defined as resistance in the absence of prior fluconazole exposure. Seconistance occurs as a result of treatment with fluconazole. Clinical failure refers to persistence or progression of oropharyng

ndidiasis despite antifungal therapy. Factors that can affect clinical response include the immune status of the patient,herence to antifungal therapy, and the potential presence of biofilms formed by Candida organisms[6]. Most patients whoperience clinical failure with fluconazole will have Candida species isolates that show in vitro resistance to fluconazole[6,1ntrast, patients in whom fluconazole-resistant Candida is isolated will often still respond clinically to fluconazole[15].










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evention of Fluconazole-Resistant Candidiasisventing fluconazole-resistant candidiasis is best achieved by avoiding unnecessary use of fluconazole or other systemic

tifungal agents and by maximizing the patient's immune status with effective antiretroviral therapy[16,17]. In addition, mperts do not recommend chronic maintenance therapy following an episode of oropharyngeal candidiasis, or with recurrensodes of oropharyngeal candidiasis[16]. Patients with cryptococcal meningitis or recurrent esophageal candidiasis require

ntinuous fluconazole therapy, but systemic antifungal therapy can usually be avoided in patients with less advanced HIV dd for less serious fungal infections.

commended Therapy for Fluconazole-Resistant Candidiasise Guidelines for Prevention and Treatment of Opportunistic Infections in Adults and Adolescents provides recommendedferred and alternative treatment options for fluconazole-refractory oropharyngeal and esophageal candidiasis (Figure 5)

ese guidelines give the highest rating for itraconazole (Sporanox ) oral solution and posaconazole (Noxafil ) oral solution. Tportunistic infections guidelines do not provide a specific duration of therapy, but most experts would recommend at leastys of therapy for patients with fluconazole-refractory oropharyngeal candidiasis, with extension of the treatment course if ponse is not complete at day 10. Patients with esophageal candidiasis should generally receive a minimum of 21 days of rapy. A number of effective intravenous options are effective, including the following intravenous antifungals: deoxycholaphotericin B ( Amphocin, Fungizone), amphotericin B lipid complex ( Abelcet ), liposomal amphotericin B ( AmBisome),cafungin (Mycamine), caspofungin (Cancidas), anidulafungin (Eraxis), and voriconazole (Vfend ). In addition, voriconazole o available in an oral form and it has excellent bioavailability.

pical Therapy Studiesailable treatment options for fluconazole-refractory oropharyngeal candidiasis include topical therapy, oral systemic agentravenous therapy. Amphotericin B oral suspension is the best-studied topical therapy for fluconazole-resistant candidiasis

TG Study 295, patients with refractory oral candidiasis (after 14 days of treatment with oral fluconazole 200 mg once dailyeived amphotericin B oral suspension (100 mg/ml) 5 ml swish and swallow four times daily; 23 (43%) of 54 subjectsponded by day 28[18]. Unfortunately, topical amphotericin B is no longer commercially available. Topical therapy withtrimazole or nystatin has not usually produced good results.

stemic Therapy Studiesveral reports have described clinical responses to treatment-refractory candidiasis with high-dose fluconazole, but typicallistance will eventually emerge[19]. Several reports have shown good efficacy with itraconazole (Sporanox ) oral solution a dose of 100 to 200 mg per day in patients with refractory oropharyngeal candidiasis [11,20,21]. The oral solution shoulshed in the mouth and then swallowed, as it probably has some topical effect in addition to its systemic effect. In the larg

al involving itraconazole solution, 41 (55%) of 74 patients who failed fluconazole therapy (200 mg once daily) achieved anical response by day 28 when treated with itraconazole oral solution (100 mg bid), with 7 days as the median timeresponse[21]. One study involving 176 HIV-infected patients with fluconazole-refractory oropharyngeal or esophagealndidiasis reported good response rates with oral posaconazole[22]. Studies with voriconazole have shown good in vitro ac

ainst fluconazole-susceptible and fluconazole-resistant strains of Candida[23][21]. Investigators found voriconazole (200 bid) to be at least as effective as fluconazole in the treatment of esophageal candidiasis, but this study did not involve

conazole-refractorycandidiasis[24]. Clinicians have used low dose (0.3 mg/kg/day) intravenous amphotericin B for fluconaractory oropharyngeal candidiasis with good success rates[14], but intravenous amphotericin B has significant adverse efen when given at a lower dose. Although intravenous liposomal amphotericin B preparations would likely provide goodponses, they are significantly more expensive than amphotericin B. In vitro studies with caspofungin have shown excellenivity against fluconazole-resistant isolates[25] and clinical studies have shown good responses with caspofungin in patienh esophagealcandidiasis[26], including fluconazole-refractory cases[27]. Although caspofungin is generally better toleratn amphotericin B[26], it is very expensive.

eferences


1. Powderly WG, Mayer KH, Perfect JR. Diagnosis and treatment of oropharyngeal candidiasis in patients infected with Hcritical 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 andfluconazole susceptibility patterns of yeast isolates colonizing the oral cavities of HIV-infected patients in the era of hactive 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-infadults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Associa





























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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-infpatients. 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 withAIDS: 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.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 albicansassociated with trends toward reduced rates of carriage of fluconazole-resistant C. albicans in human immunodeficievirus-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 thesemechanisms 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. Heterogeneousmechanisms of azole resistance in Candida albicans clinical isolates from an HIV-infected patient on continuousfluconazole 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 isofrom human immunodeficiency virus-infected patients with oropharyngeal candidiasis. Antimicrob Agents Chemother2002;46:1695-703.[PubMed Abstract]

11. Koks CH, Meenhorst PL, Bult A, Beijnen JH. Itraconazole solution: summary of pharmacokinetic features and review activity in the treatment of fluconazole-resistant oral candidosis in HIV-infected persons. Pharmacol Res. 2002;46:19201.[PubMed Abstract]

12. Pfaller MA, Boyken LB, Hollis RJ, Kroeger J, Messer SA, Tendolkar S, Diekema DJ. Validation of 24-hour fluconazole Mreadings versus the CLSI 48-hour broth microdilution reference method: results from a global Candida antifungalsurveillance 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 tfuture 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 tAntimicrob Agents Chemother. 1993;37:2449-53.[PubMed Abstract]

15. Revankar SG, Kirkpatrick WR, McAtee RK, et al. Detection and significance of fluconazole resistance in oropharyngeacandidiasis 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 wHIV: 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 updatthe 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 forfluconazole-refractory oral candidiasis in persons with HIV infection. Adult AIDS Clinical Trials Group Study Team 295AIDS. 2000;14:845-52.[PubMed Abstract]

19. Revankar SG, Dib OP, Kirkpatrick WR, et al. Clinical evaluation and microbiology of oropharyngeal infection due tofluconazole-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 fluconazole

refractory 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 itraconaoral 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 andesophageal 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 afluconazole in the treatment of esophageal candidiasis in immunocompromised patients. Clin Infect Dis. 2001;33:14454.[PubMed Abstract]

25. Pfaller MA, Messer SA, Boyken L, Rice C, Tendolkar S, Hollis RJ, Diekema DJ. Caspofungin activity against clinical isoof 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 esophagcandidiasis resistant to fluconazole. J Acquir Immune Defic Syndr. 2002;31:183-7.[PubMed Abstract]

iagnosis and Management of Tuberculosis Immune Reconstitution

nflammatory Syndrome (TB-IRIS)

thors: G. Manoharan, MDChristopher Behrens, MD

Clinical Associate Professor

University of Washington School of MedicineDepartments of Global Health and Medicine

Medical Director, International Training & Education Center on Health

Disclosure: None

earning Objectives

4-year-old HIV-infected man from southern India is diagnosed with pulmonary tuberculosis (TB) based on symptoms of moptysis and weight loss, characteristic findings on chest radiograph (Figure 1), and a sputum smear positive for acid-facilli (AFB). His absolute CD4 count at the time of diagnosis is 60 cells/mm 3, and he has never taken antiretroviral therapy.rted on anti-TB therapy consisting of isoniazid, rifampin, ethambutol, and pyrazinamide. Two months later, he has a norm

est radiograph (Figure 2) and his sputum is negative on AFB staining. At that time, he begins antiretroviral therapy with a































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

agnosis and Case Definition of TB-IRISe diagnosis of TB-IRIS is rarely straightforward, as no single laboratory test can establish or rule out TB-IRIS. To establisovisional diagnosis of TB-IRIS, clinicians must rely upon a combination of clinical signs and symptoms, laboratory findings,elihood of other conditions, and clinical judgment. In 2008, a panel of expert clinicians convened in Kampala, Uganda to

mulate a case definition of TB-IRIS that could be practically applied in resource-limited settings [14]. The Internationaltwork for the Study of HIV-associated IRIS panel distinguished between ―paradoxical TB-IRIS‖ (worsening of previouslygnosed TB disease in a person with HIV infection who initiates antiretroviral therapy) and "unmasking TB-IRIS" (clinicalnifestations of previously undiagnosed TB in a person with HIV infection who initiates antiretroviral therapy). This panel reed by consensus on a case definition and a provisional case definition for paradoxical TB-IRIS (Figure 4) and unmaskinS (Figure 5). The case definitions deliberately exclude the use of laboratory tests, such as CD4 and viral load testing,ognizing that clinicians managing HIV-infected persons in resource-limited settings do not routinely have access to such t

vestigators subsequently validated these case definitions in cohort studies in Thailand [15] and South Africa [16,17], andfinitions remain the most useful case definitions for application in resource-limited settings.

ming of Antiretroviral Therapy with Known TBcently released data from three randomized trials suggest that although delaying the initiation of antiretroviral therapy intients with HIV and TB coinfection reduces the risk of TB-IRIS, this approach correlates with higher mortality rates when

mpared with earlier initiation of antiretroviral therapy, especially in patients with low CD4 counts[18,19,20]. The WHOdelines therefore recommend starting antiretroviral therapy as soon as tuberculosis therapy is tolerated —specifically, aspossible (and within 8 weeks) of initiation of anti-TB therapy [21,22].

e of Corticosteroids in TB-IRISmerous anecdotal reports and small case series have suggested corticosteroids help reduce inflammation in the setting ofS. Specific formulations and doses used in reports have included intravenous methylprednisolone 40 mg every 12 hours dnisone 20 to 70 mg per day. The length of steroid administration and the use of a steroid taper have also

ried considerably[12]. In the only randomized controlled trial that has evaluated the safety and efficacy of corticosteroids -IRIS, investigators randomized 110 South African HIV-infected persons with evidence of paradoxical TB-IRIS to receive ecebo 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/da

weeks)[23] . The study excluded patients with life-threatening manifestations of TB-IRIS. The primary combined endpointspitalized plus therapeutic outpatient procedures) was significantly lower in patients randomized to the corticosteroid armeks two and four of the study, patients who received corticosteroids had higher Karnofsky scores, higher quality of life sco

re frequent improvement in chest radiograph findings, and fewer symptoms, when compared with patients who receivedcebo (Figure 6 series). Severe infections occurred with equal frequency in the two groups. Corticosteroid therapy was riated in 10 patients after 4 weeks, suggesting that some patients may require an extended course of corticosteroids.

sk of Drug-Resistant TB in Patients with Suspected TB-IRISa recent cohort study of South African patients, 10% of the patients with suspected TB-IRIS were found to have previousldiagnosed rifampicin-resistant TB[24]. Hence, drug resistance should ideally be ruled out in patients with active TB and asentation consistent with TB-IRIS, especially if administration of corticosteroids is being considered.

commendations for the Management of TB-IRISdence-based guidelines for the management of suspected or confirmed TB-IRIS in resource-limited setting do not yet exising to the scarcity of randomized controlled trials evaluating management approaches. Nevertheless, we recommend theowing 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-limitedsettings. Because no definitive test for TB-IRIS exists, clinicians should consider alternative diagnoses in patients wsuspected TB-IRIS, especially if the severity of the condition warrants administering corticosteroids. Clinicians shouideally evaluate the patient for drug-resistant TB, as cases of multidrug-resistant-TB have been identified in patientsTB-IRIS.

Most cases of TB-IRIS have a self-limited course and will resolve with continuing treatment with little or no change inoverall management. Use of non-steroidal anti-inflammatory agents may provide adequate relief of symptoms in milcases, 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 regis inadequate (for example if MDR-TB is suspected, or drug-drug interactions could result in suboptimal serum anti-Tdrug levels).

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In nearly all cases, the patient with TB-IRIS should remain on antiretroviral therapy. Certain circumstances, howevemay require temporary interruption of antiretroviral therapy, such as when life-threatening complications of IRIS dev(e.g. increasing intracranial pressure in the setting of TB meningitis, or an expanding abscess that compromises thepatient‘s 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 TBcases when patients have persistent fever, abscesses, meningitis, or dyspnea.

The dosing and duration of corticosteroids should be tailored to individual patient circumstances. We recommend pawith moderate to severe TB-IRIS receive prednisone dosed at 1.5 mg/kg/day for 2 weeks, followed by a taper of 0.7

mg/kg/day over 2 additional weeks. Some patients, particularly those with very high mycobacterial loads or severe cdeterioration, may require prolonged courses of corticosteroids.

The patient receiving corticosteroids for TB-IRIS should undergo careful monitoring for response to corticosteroidtherapy. If the patient‘s clinical condition does not improve, the clinician should consider an alternative diagnosis anpossible termination of corticosteroids, since administering corticosteroids to a patient with a non-tuberculousopportunistic infection or disease could result in further clinical deterioration. Ideally, the clinician should rule out drresistant TB before administering corticosteroids.

eferences


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 immunologicalclassification 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 apublic 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 puhealth approach: 2010 revision. WHO, 2010.[World Health Organization]

5.

http://www.who.int/hiv/pub/vct/hivstaging/en/index.html



http://www.who.int/hiv/pub/arv/adult2010/en/index.html



http://www.who.int/hiv/pub/paediatric/infants2010/en/index.html








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 Colleg

Vellore, India

8. 9. Figure 2. Chest Radiograph in Patient with Pulmonary Manifestations of TB-IRIS

s chest radiograph shows a large right-sided pleural effusion and scattered patchy infiltrates that developed as a result of

S.



gure 3. Pericardial Effusion in Patient with and TB-IRIS

s chest radiograph shows a patient with TB prior to receiving antiretroviral therapy (Panel A) and the same patient with

ge pericardial effusion (Panel B) 2 months after receiving antiretroviral therapy.

urce: 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 syndrom

case definitions for use in resource-limited settings. Lancet Infect Dis. 2008;8:516–23.



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 syndro

case definitions for use in resource-limited settings. Lancet Infect Dis. 2008;8:516–23.

17.



18. Figure 6: Efficacy and Safety of a Four-week Course of Corticosteroids for HIV-Infected Persons with Paradoxical TB

in South Africa.

Image 1. Study Title and Source

IDS Education and Training Centers National Resource Centerww.aids-etc.org

s website provides information related to HIV news and events, educational and training platform materials, and providerources for special populations. In addition, the site provides links to each of the AIDS Educational and Training Centers inted States (AIDS Services and Contacts). Use of this site does not require log in.

IDSinfoww.aidsinfo.nih.gov s website is a service funded by the U.S. Department of Health and Human Services (DHHS) and serves as the major siteerally-funded guidelines related to the medical management of HIV. The guideline topics include antiretroviral therapy,portunistic infections, maternal-child transmission, and postexposure prophylaxis. Use of this site does not require log in.

merican Academy of HIV Medicine (AAHIVM)ww.aahivm.org/

s organization is the largest organization of HIV frontline providers and it has served as a leader in establishing the HIVecialist credentialing process. This site provides very useful information regarding the credentially process and the academf-Directed Medicine Education Program, including the Core Curriculum, the HIV Medicine Self-Directed Study Guide, and aucational workshop series.

inical Care Options for HIVww.clinicaloptions.com/hiv s website provides an array of services, including updated news information, clinical management series, online CME,atment updates, conference updates, and annual course updates. Use of this site requires log in, but is free.

IV InSitetp://hivinsite.ucsf.edu s site provides free access the HIV InSite Knowledge Base, a comprehensive, on-line textbook of HIV disease from theversity of California San Francisco and San Francisco General Hospital. In addition, the site provides new and noteworthydical information, a newswatch, and substantial information related to prevention of HIV. Use of this site does not require

IV Medicine Association (HIVMA)tp://www.hivma.org/ s organization was created by the Infectious Diseases Society of America for medical professions engaged in HIV medicins site provides information regarding education, training, practice guidelines, prevention, and public policy. This site also VMA‘s definition of an experience HIV provider.

nternational AIDS Society-USAtp://www.iasusa.org e International AIDS Society-USA Website offers free continuing medical education to physicians who provide care for peoh HIV/AIDS. Online services include Cases on the Web, a monthly CME case study, podcasts and Webcasts of IAS-USA livurses, and access to Topics in HIV Medicine, the IAS-USA peer-reviewed journal as well as access to treatment guidelines rting antiretroviral therapy, resistance testing, and HIV mutations.

ohns Hopkins AIDS Serviceww.hopkins-aids.edu s website provides timely literature reviews (article summaries) and access to the bimonthly newsletter, Hopkins HIV Repe site has an extensive section on prevention of HIV. Dr. Joel Gallant provides a very interesting expert Q & A that includenician Forum and a Patient Forum. Use of this site does not require log in.

http://www.aids-etc.org/


http://www.aidsinfo.nih.gov/


http://www.aahivm.org/


http://www.clinicaloptions.com/hiv


http://hivinsite.ucsf.edu/


http://www.hivma.org/


http://www.iasusa.org/


http://www.hopkins-aids.edu/












edscape HIV/AIDSww.medscape.com/hiv-aidshome s website is one of the many subspecialty Medscape websites and it provides news information, expert reviews and

mmentary, and numerous CME topics, conference summaries, ask the expert topics, a antiretroviral reference guide, andtient education resources. Use of this site requires log in, but is free.

ational HIV/AIDS Clinicians’ Consultation Center (NCCC) ww.ucsf.edu/hivcntr

s website provides general information regarding the NCCC, a service that includes the National HIV Telephone Consultatrvice ("Warmline") and the National Clinicians‘ Post-Exposure Prophylaxis Hotline ("PEPline"). The site also contains usefunsultation resources, training materials, archived newsletters, and answers to commonly asked questions regardingstexposure prophylaxis, and resistance testing consultation panel case reports. Use of this site is free and no registration uired.

http://www.medscape.com/hiv-aidshome


http://www.ucsf.edu/hivcntr




Case Study HIV With Diarrhea

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