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.