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HIV/AIDS Opportunistic Infection Update David H. Spach, MD Medical Director Northwest AIDS Education and Training Center Associate Professor of Medicine Division of Infectious Diseases University of Washington, Seattle. DHS/HIV/ARV Rx/PP. Opportunistic Infection: Update.

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Dhs hiv arv rx pp

HIV/AIDS Opportunistic Infection UpdateDavid H. Spach, MDMedical DirectorNorthwest AIDS Education and Training CenterAssociate Professor of MedicineDivision of Infectious DiseasesUniversity of Washington, Seattle

DHS/HIV/ARV Rx/PP


Opportunistic infection update

Opportunistic Infection: Update

  • Pneumocytis pneumonia

  • Toxoplasmosis

  • Mycobacteriumavium complex

  • Cytomegalovirus

  • Esophageal candidiasis

  • Cryptococcal meningitis

  • Cryptosporidiosis

DHS/HIV/ARV RX/PP


Dhs hiv arv rx pp

Pneumocystis Pneumonia

DHS/HIV/PP


Pneumocystis pneumonia new developments

Pneumocystis PneumoniaNew Developments

  • Basic Science- Pneumocystiscarinii changed to Pneumocystisjiroveci*- Characterization of 14- demethylase enzyme

  • Epidemiology- Reactivation of latent organisms versus acute acquisition

  • New Diagnostics- PCR-based test on oral washes

  • Resistance to TMP-SMX- Mutations identified in dihydropterate synthase (DHPS)- Presence of mutation associated with increased mortality

  • Immune Reconstitution- Marked inflammatory response about 15-30 days after HAART

*Pronounced “yee row vet zee” & named after the Czech pathologist Otto Jirovec

DHS/HIV/Clin Manifestations/PP


Pneumocystis lanosterol 14 demethylase

Pneumocystis: Lanosterol 14- Demethylase

Ergosterol Biosynthesis

Lanosterol 14- Demethylase (Erg 11)

Inherent Azole Resistance

Ergosterol

Cytoplasmic Membrane

From: Morales IJ, et al. Am J Respir Mol Bio 2003;Feb 26 (e-Publication).


Pneumocystis in asymptomatic individuals

Pneumocystis in Asymptomatic Individuals

  • Methods- N = 16 HIV-infected patients- BAL samples (n = 47)- Genotyping of P. jiroveci

  • Results- 35/47 from patients positive for P. jiroveci- 7 with P. jiroveci 7-10 months after acute PCP; all 7 had different genotype at follow-up than found during acute PJP- TMP-SMX did not always clear infection

From: Wakefield AE et al. J Infect Dis 2003;187:901-8.

DHS/ HIV/PP


Discontinuation of pcp prophylaxis recommendations from usphs idsa guidelines

Discontinuation of PCP ProphylaxisRecommendations from USPHS/IDSA Guidelines

Criteria

Setting

Primary Prophylaxis

Secondary Prophylaxis

CD4 > 200 for > 3 months

CD4 > 200 for > 3 months

From: MMWR 2001;50 (RR-11):1-52.

DHS/HIV/OIs/PP


Pneumocystis immune reconstitution

Pneumocystis & Immune Reconstitution

  • Timing- Typically 7 to 30 days after starting HAART

  • Clinical Manifestations- High grade-fever- Patchy infiltrates- BAL: few Pneumocystis organisms, severe inflammatory foci

  • Treatment- Restart corticosteroids

From: Wislez M et al. Am J Respir Crit Care Med 2001;164:847-51.

DHS/ HIV/PP


Dhs hiv arv rx pp

Toxoplasmosis

DHS/HIV/PP


Discontinuation of toxoplasmosis prophylaxis recommendations from usphs idsa guidelines

Discontinuation of Toxoplasmosis ProphylaxisRecommendations from USPHS/IDSA Guidelines

Criteria

Setting

CD4 > 200 for > 3 months

CD4 > 200 for > 6 months

and

Completed Initial Rx

and

Asymptomatic for Toxo

Primary Prophylaxis

Secondary Prophylaxis

From: MMWR 2001;50 (RR-11):1-52.

DHS/HIV/OIs/PP


Dhs hiv arv rx pp

Mycobacteriumavium Complex

DHS/HIV/PP


Mac immune reconstitution syndrome

MAC: Immune Reconstitution Syndrome

  • Low CD4 (< 50): more severe illness; fevers, weight loss, leukocytosis, positive blood cultures (Race, Lancet, 1998)

  • High CD4 (> 100-150): fewer systemic symptoms, more localized suppurative disease (Phillips, JAIDS, 1998)

  • Treatment: continue HAART and MAC therapy, NSAIDS, steroids (for severe symptoms), local surgery?

Slide From Bob Harrington, MD

DHS/ID/Cases/PP


Discontinuation of mac prophylaxis recommendations from usphs idsa guidelines

Discontinuation of MAC ProphylaxisRecommendations from USPHS/IDSA Guidelines

Criteria

Setting

Primary Prophylaxis

Secondary Prophylaxis

CD4 > 100 for > 3 months

CD4 > 100 for > 6 months

and

Completed 12 months MAC RX

and

Asymptomatic for MAC

From: MMWR 2001;50 (RR-11):1-52.

DHS/HIV/OIs/PP


Dhs hiv arv rx pp

Cytomegalovirus

DHS/HIV/PP


Valganciclovir valcyte induction therapy for cmv retinitis

Valganciclovir (Valcyte)Induction Therapy for CMV Retinitis

Study Design

Week 4: Non-progression

  • Methods - N = 160 - Newly diagnosed CMV retinitis

  • Regimens - Valganciclovir: 900 mg PO bid x 21d, 900 mg PO qd x 7d - Ganciclovir: 5 mg/kg IV bid x 21d, 5 mg/kg IV qd x 7d

From: Martin DF et al. N Engl J Med 2002;346:1119-26.

DHS/OIs/HIV


Discontinuation of cmv prophylaxis recommendations from usphs idsa guidelines

Discontinuation of CMV ProphylaxisRecommendations from USPHS/IDSA Guidelines

Criteria

Setting

Primary Prophylaxis

Secondary Prophylaxis

Not Applicable

CD4 > 100-150 for > 6 months

and

No evidence of active disease

and

Regular ophtho examinations

From: MMWR 2001;50 (RR-11):1-52.

DHS/HIV/OIs/PP


Dhs hiv arv rx pp

Esophageal Candidiasis

DHS/HIV/PP


Fluconazole mechanism of action

Fluconazole: Mechanism of Action

Ergosterol Biosynthesis

Lanosterol 14- Demethylase

Fluconazole

Ergosterol

Cytoplasmic Membrane


Fluconazole mechanism of resistance

Fluconazole: Mechanism of Resistance

Ergosterol Biosynthesis

Altered Binding Site

Lanosterol 14- Demethylase

Fluconazole

Ergosterol

Efflux Pump

Fluconazole


Caspofungin mechanism of action

Caspofungin: Mechanism of Action

Beta-Glucan Synthase

Beta-Glucan Synthase

Echinocandins

Glucan Fibrils

Cytoplasmic Membrane

Cell Wall


Fluconazole resistant esophageal candidiasis treatment options

Fluconazole-Resistant Esophageal CandidiasisTreatment Options

  • Fluconazole (Diflucan)400-800 mg PO qd

  • Itraconazole Solution (Sporonox)100 mg PO bid

  • Caspofungin (Cancidas) 50-70 mg IV qd

  • Amphotericin B 0.3-0.7 mg/kg IV qd

  • Liposomal Ampho B? Optimal Dose

Dose

Drug

DHS/HIV/OIs/PP


Candida species in vitro testing

Candida Species: In Vitro Testing

  • C. albicans- Fluconazole (S)- Fluconazole (R)

  • C. glabrata- Fluconazole (S)- Fluconazole (R)

Organism

Caspofungin (MIC 50)

Fluconazole (MIC 50)

0.1640

1.2540

0.200.20

0.200.40

From: Vazquez JA et al. Antimicrob Agents Chemo 1997;41:1612-4.

DHS/HIV/OIs/PP


Caspofungin cancidas vs amphotericin treatment of esophageal candidiasis

Caspofungin (Cancidas) vs. AmphotericinTreatment of Esophageal Candidiasis

Study Design

Clinical & Endoscopic Response (ITT)

  • Methods - N = 128 (123 HIV-infected*) -*Mean CD4 = 84 cells/mm3 - Documented Candida esophagitis - Randomized, double-blind study

  • Regimens (14 days) - Caspofungin: 50 mg IV qd - Caspofungin: 70 mg IV qd - Amphotericin B: 0. 5 mg/kg IV qd

From: Villanueva A et al. Clin Infect Dis 2001;33:1529-35.

DHS/OIs/HIV


Fluconazole resistant esophageal candidiasis treatment with caspofungin

Fluconazole-Resistant Esophageal CandidiasisTreatment with Caspofungin

Study Design

Clinical Response

  • Methods - N = 14 - Esophageal candidiasis - Failed Fluconazole 200 mg/d or - Isolate with Fluconazole MIC > 16

  • Regimens - Caspofugin

  • Response - Defined as resolution of all symptoms and substantial improvement on endoscopy

From: Kartsonis NK et al. J Acquir Immune Defic Syndr 2002;31:183-7.

DHS/OIs/HIV


Dhs hiv arv rx pp

Cryptococcal Meningitis

DHS/HIV/PP


Cryptococcal meningitis 14 day induction therapy

Cryptococcal Meningitis: 14-Day Induction Therapy

Suspected or Confirmed Cryptococcal Meningitis*Serial LPs ifOpening Pressure > 200 mm H2O

1

3

2

Ampho B0.7-1.0 mg/kg/d+5-Flucytosine100 mg/kg/d

Ampho B0.7-1.0 mg/kg/d

Fluconazole400-800 mg/d

Initial LP: Reduce opening pressure by 50%Daily LPs: Maintain opening < 200 mm H2OCessation of LPs: once opening pressure normal for several consecutive days

DHS/OI/PP


Cryptococcal meningitis 10 week consolidation therapy

Cryptococcal Meningitis: 10 Week Consolidation Therapy

Cryptococcal Meningitis2 Week Lumbar Puncture with Negative Culture

1

3

2

Fluconazole400 mg/d

Ampho B0.7-1.0 mg/kg/d

Itraconazole400 mg/d

DHS/OI/PP


Cryptococcal meningitis csf pressure post treatment outcome

Cryptococcal MeningitisCSF Pressure Post-Treatment & Outcome

Study Design

Week 2 Outcome: Clinical Failure

  • Methods - N = 161 - HIV-infected - Cryptococcal meningitis - Retrospective analysis - Week 2 outcome - Compared pre/post CSF OP

  • Baseline - 60% > 250 mm H2O - 30% > 350 mm H2O

From: Graybill JR et al. Clin Infect Dis 2000;30:47-54.

DHS/OIs/HIV


Cryptococcal meningitis features of high 350 mm h 2 o csf pressure

Cryptococcal MeningitisFeatures of High (> 350 mm H2O) CSF Pressure

  • Clinical Features - More frequent headache & meningismus - More frequent papilledema & abnormal reflexes

  • Lab Features - Higher CSF Cryptococcal antigen - More frequent positive India ink

  • Outcome Features - Reduced short-term survival if CSF pressure > 250

From: Graybill JR et al. Clin Infect Dis 2000;30:47-54.

DHS/OIs/HIV


Cryptococcal meningitis strategies for reducing high csf pressure

Cryptococcal MeningitisStrategies for Reducing High CSF Pressure

  • Lumbar Puncture - 18 gauge needle - Drained until CSF pressure < 200 mm H2O - Repeat as often as needed

  • Medical Therapy - Corticosteroids? - Acetazolamide? - Mannitol?

From: Graybill JR et al. Clin Infect Dis 2000;30:47-54.

DHS/OIs/HIV


Cryptococcal meningitis acetazolamide for reducing high csf pressure

Cryptococcal MeningitisAcetazolamide for Reducing High CSF Pressure

  • Background - N = 22 Thai HIV-infected - Confirmed cryptococcal meningitis - CSF pressure > 200 mm H2O - Randomized, placebo-controlled

  • Regimens - Acetazolamide versusPlacebo

  • Results - No benefit, trial stopped secondary adverse effects

From: Newton PN et al. Clin Infect Dis 2002;35:769-72.

DHS/OIs/HIV


Dhs hiv arv rx pp

Cryptosporidiosis

DHS/HIV/PP


Cryptosporidiosis in hiv aids combination therapy

Cryptosporidiosis in HIV/AIDSCombination Therapy

  • Study Design- N = 13- CD4 count < 100 cells/mm3 (median 30 cells/mm3) - Chronic cryptosporidiosis (median duration 12 weeks)

  • Regimen- Paromomycin 1g bid + Azithromycin 600 mg qd x 28d followed by Paromomycin 1g bid x 12 weeks

From:Smith NH et al. J Infect Dis 1998;178:900-3.

DHS/HIV/Clin Manifestations/PP


Cryptosporidiosis combination therapy

Cryptosporidiosis: Combination Therapy

Stool Frequency

Oocyst Excretion

From: Smith NH et al. J Infect Dis 1998;178:900-3.

DHS/HIV/OIs/PP


Cryptosporidiosis nitazoxanide therapy

Cryptosporidiosis:Nitazoxanide Therapy

Study Design

Response

  • Methods - N = 100 (50 adults, 50 children) - Cryptosporidiosis diarrhea - HIV testing not performed

  • Regimens* - Nitazoxanide: 500 mg bid x 3d - Placebo: bid x 3d

Children- Age 4-11 yrs: 200 mg bid x 3d- Age 1-3 yrs: 100 mg bid x 3d

From: Rossignol J-F et al. J Infect Dis 2001;184:103-6.

DHS/OIs/HIV


Cryptosporidiosis treatment

Cryptosporidiosis: Treatment

  • HAART

  • Antimicrobial Agents- Paromomycin- Azithromycin- Nitazoxanide

  • Antimotility Agents

From: Chen X-M, et al. N Engl J Med 2002;346;1723-31.

DHS/HIV/ARV RX/PP


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