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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. - PowerPoint PPT Presentation
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April 2003
DHS/HIV/ARV Rx/PP
HIV/AIDS Opportunistic Infection Update
David H. Spach, MD
Medical DirectorNorthwest AIDS Education and Training Center
Associate Professor of MedicineDivision of Infectious Diseases
University of Washington, Seattle
April 2003
DHS/HIV/ARV RX/PP
Opportunistic Infection: Update
Pneumocytis pneumonia
Toxoplasmosis
Mycobacterium avium complex
Cytomegalovirus
Esophageal candidiasis
Cryptococcal meningitis
Cryptosporidiosis
April 2003
DHS/HIV/PP
Pneumocystis Pneumonia
April 2003
Pneumocystis PneumoniaNew Developments
Basic Science- Pneumocystis carinii changed to Pneumocystis jiroveci* - 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
DHS/HIV/Clin Manifestations/PP
*Pronounced “yee row vet zee” & named after the Czech pathologist Otto Jirovec
April 2003
Pneumocystis: Lanosterol 14- Demethylase
Ergosterol BiosynthesisLanosterol 14- Demethylase (Erg 11)
Ergosterol
Cytoplasmic Membrane
From: Morales IJ, et al. Am J Respir Mol Bio 2003;Feb 26 (e-Publication).
Inherent Azole Resistance
April 2003DHS/ HIV/PP
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.
April 2003
Discontinuation of PCP ProphylaxisRecommendations from USPHS/IDSA Guidelines
DHS/HIV/OIs/PP
Setting
Primary Prophylaxis
Secondary Prophylaxis
CD4 > 200 for > 3 months
CD4 > 200 for > 3 months
Criteria
From: MMWR 2001;50 (RR-11):1-52.
April 2003DHS/ HIV/PP
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.
April 2003
DHS/HIV/PP
Toxoplasmosis
April 2003
Discontinuation of Toxoplasmosis ProphylaxisRecommendations from USPHS/IDSA Guidelines
Setting
Primary Prophylaxis
Secondary Prophylaxis
CD4 > 200 for > 3 months
CD4 > 200 for > 6 months
and
Completed Initial Rx
and
Asymptomatic for Toxo
Criteria
From: MMWR 2001;50 (RR-11):1-52. DHS/HIV/OIs/PP
April 2003
DHS/HIV/PP
Mycobacterium avium Complex
April 2003
MAC: Immune Reconstitution Syndrome
DHS/ID/Cases/PP
• 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
April 2003
Discontinuation of MAC ProphylaxisRecommendations from USPHS/IDSA Guidelines
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
Criteria
From: MMWR 2001;50 (RR-11):1-52. DHS/HIV/OIs/PP
April 2003
DHS/HIV/PP
Cytomegalovirus
April 2003DHS/OIs/HIV
Valganciclovir (Valcyte) Induction Therapy for CMV Retinitis
90%
0
20
40
60
80
100
No
n-p
rog
ress
or
%
Valganciclovir (PO) Ganciclovir (IV)
90%
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
Study Design Week 4: Non-progression
From: Martin DF et al. N Engl J Med 2002;346:1119-26.
April 2003
Discontinuation of CMV ProphylaxisRecommendations from USPHS/IDSA Guidelines
Setting
Primary Prophylaxis
Secondary Prophylaxis
Not Applicable
CD4 > 100-150 for > 6 months
and
No evidence of active disease
and
Regular ophtho examinations
Criteria
From: MMWR 2001;50 (RR-11):1-52. DHS/HIV/OIs/PP
April 2003
DHS/HIV/PP
Esophageal Candidiasis
April 2003
Fluconazole: Mechanism of Action
Fluconazole
Ergosterol BiosynthesisLanosterol 14- Demethylase
Ergosterol
Cytoplasmic Membrane
April 2003
Fluconazole: Mechanism of Resistance
Fluconazole
Ergosterol BiosynthesisLanosterol 14- Demethylase
Ergosterol
Efflux Pump
Altered Binding Site
Fluconazole
April 2003
Caspofungin: Mechanism of Action
Cell WallCytoplasmic Membrane
Glucan Fibrils
Beta-Glucan Synthase Beta-Glucan SynthaseEchinocandins
April 2003
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
DHS/HIV/OIs/PP
Drug Dose
April 2003
Candida Species: In Vitro Testing
C. albicans
- Fluconazole (S)
- Fluconazole (R)
C. glabrata
- Fluconazole (S)
- Fluconazole (R)
DHS/HIV/OIs/PP
0.16
40
1.25
40
Organism Fluconazole (MIC 50)
0.20
0.20
0.20
0.40
Caspofungin (MIC 50)
From: Vazquez JA et al. Antimicrob Agents Chemo 1997;41:1612-4.
April 2003
DHS/OIs/HIV
Caspofungin (Cancidas) vs. AmphotericinTreatment of Esophageal Candidiasis
85%
96%
72% 74%
89%
63%
0
20
40
60
80
100
Fa
vo
rab
le R
es
po
ns
e
End of Rx 14 Day Post Rx
Caspofungin 50 mg
Caspofungin 70 mg
Amphotericin B
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
Study Design Clinical & Endoscopic Response (ITT)
From: Villanueva A et al. Clin Infect Dis 2001;33:1529-35.
April 2003
DHS/OIs/HIV
Fluconazole-Resistant Esophageal CandidiasisTreatment with Caspofungin
0
20
40
60
80
100
Cli
nic
al
Res
po
ns
e
Caspofungin
79%
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
Study Design Clinical Response
From: Kartsonis NK et al. J Acquir Immune Defic Syndr 2002;31:183-7.
April 2003
DHS/HIV/PP
Cryptococcal Meningitis
April 2003
Cryptococcal Meningitis: 14-Day Induction Therapy
DHS/OI/PP
Initial LP: Reduce opening pressure by 50%Daily LPs: Maintain opening < 200 mm H2OCessation of LPs: once opening pressure normal for several consecutive days
Ampho B0.7-1.0 mg/kg/d
+5-Flucytosine100 mg/kg/d
Suspected or Confirmed Cryptococcal Meningitis*Serial LPs if Opening Pressure > 200 mm H2O
Ampho B0.7-1.0 mg/kg/d
Fluconazole400-800 mg/d
2 31
April 2003
Cryptococcal Meningitis: 10 Week Consolidation Therapy
DHS/OI/PP
Itraconazole400 mg/d
Cryptococcal Meningitis2 Week Lumbar Puncture with Negative Culture
Ampho B0.7-1.0 mg/kg/d
Fluconazole400 mg/d
2 31
April 2003DHS/OIs/HIV
Cryptococcal MeningitisCSF Pressure Post-Treatment & Outcome
4%
20%
0
5
10
15
20
25
30
Clin
ical
Fai
lure
CSF Pressure: Decrease > 10
CSF Pressure: No Change CSF Pressure: Increase > 10
2%
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
Study Design Week 2 Outcome: Clinical Failure
From: Graybill JR et al. Clin Infect Dis 2000;30:47-54.
April 2003DHS/OIs/HIV
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.
April 2003DHS/OIs/HIV
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.
April 2003DHS/OIs/HIV
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.
April 2003
DHS/HIV/PP
Cryptosporidiosis
April 2003
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
April 2003
Cryptosporidiosis: Combination Therapy
Stool Frequency Oocyst Excretion
6.5
4.9
3.0
0
2
4
6
8
Sto
ols
/Day
Baseline
Week 4
Week 12
43
7.3 3.00
10
20
30
40
50
24-h
Oo
cyst
s x
106
Baseline
Week 4
Week 12
From: Smith NH et al. J Infect Dis 1998;178:900-3. DHS/HIV/OIs/PP
April 2003DHS/OIs/HIV
Cryptosporidiosis:Nitazoxanide Therapy
80%
41%
67%
22%
0
20
40
60
80
100
Res
po
nse
%
Diarrhea Resolved Oocysts Cleared
Nitazoxanide Placebo Methods - N = 100 (50 adults, 50 children) - Cryptosporidiosis diarrhea - HIV testing not performed
Regimens* - Nitazoxanide: 500 mg bid x 3d - Placebo: bid x 3d
Study Design Response
From: Rossignol J-F et al. J Infect Dis 2001;184:103-6.
Children- Age 4-11 yrs: 200 mg bid x 3d- Age 1-3 yrs: 100 mg bid x 3d
April 2003
DHS/HIV/ARV RX/PP
Cryptosporidiosis: Treatment
• HAART
• Antimicrobial Agents- Paromomycin- Azithromycin- Nitazoxanide
• Antimotility Agents
From: Chen X-M, et al. N Engl J Med 2002;346;1723-31.