April 2003 DHS/HIV/ARV Rx/PP 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
Jan 19, 2016
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.