hiv-associated opportunistic infections 2009

HIV-Associated Opportunistic Infections 2009

Robert D. Harrington, M.D.

University of Washington

MMWR 1981

1

10

100

1,000

10,000

100,000

1,000,000

10,000,000

Plasma HIV RNA

MAC, CMV, PML, PCNSL, Cryptococcus, MicrosporidiaToxo

PCP

4-8 Weeks Up to 12 Years 2-3 Years

CD4 Cell Count

1,000

500

CD4 Count and Opportunistic Infections

200

100

Bacterial Pneumonia, TB, HSV, Cryptosporidiosis

Thrush, lymphoma, KS

Opportunistic Infections and Geography

Common OIs• PCP• MAC• Candida

Regional Effects• Southwest:

– Coccidiodomycosis

• Midwest:– Histoplasmosis and

Blastomycosis

• South: – Blastomycosis and

Toxoplasmosis

North America

Opportunistic Infections and Geography

The World

TBBacteriaMalariaCryptococcus

CandidaPCPMAC

Holmes, CID, 03Putong, SEA Trop Med, 02Margues, Med Mycol, 2000Amornkul, CID, 03

PCPTBCandidaCryptococcusPenicilliosis

PCPTBCryptococcusIsosporaCryptosporidiosisMicrosporidia

PCP, TBCandida, MACCryptococcusLeishmaniasis

Prophylaxis to Prevent Opportunistic Infections

Considerations for Prophylaxis

• Infection should be common and/or predictable

• Infection should be clinically significant

• Treatment (prophylaxis) should be effective, non-toxic and affordable

Prophylaxis to Prevent Opportunistic Infections in the Developed World

PrimaryPCP CD4 < 200

MTb PPD > 5mm

Toxo IgG+,CD4 < 100

MAC CD4 < 50

VZV Exposure with IgG- or no hstry

S. pneumoniae

HBV

HAV

Influenza

SecondaryPCP

Toxo

MAC

CMV

Cryptococcosis

Histoplasmosis

Coccidioidomycosis

Salmonella species bacteremia

Recurrent HSV

Recurrent Candidiasis

Effect of HAART on Opportunistic Infections: Reduced Need for Prophylaxis

Primary Prophylaxis

PCP When CD4 > 200 for 3 months

MAC When CD4 > 100 for 3 months

Toxo When CD4 > 200 for 3 months

Effect of HAART on Opportunistic Infections: Reduced Need for Prophylaxis

Secondary Prophylaxis or Maintenance TherapyPCP When CD4 > 200 for 3 monthsCMV When CD4 > 100-150 for 6 months,

retinal disease stable and not sight-threatening

MAC When CD4 > 100 for 6 months, no symptoms of MAC and after 12

months of MAC RxToxo When CD4 > 200 for 6 months and

completed initial Toxo RxCryptococcus When CD4 > 100-200 for 6 months

and completed initial Crypto Rx

HIV ASSOCIATED MALIGNANCIES

AIDS Defining Malignancies

• Kaposi’s sarcoma

• Primary CNS lymphoma (PCNSL)

• Non-Hodgkin’s lymphoma (NHL)

• Invasive cervical cancer

HIV ASSOCIATED MALIGNANCIES

• Hodgkin’s disease• Anal cancer• Multiple myeloma• Leukemia• Lung cancer

• Head and neck tumors• GI malignancies• Genital cancers• Hypernephroma• Soft tissue tumors

Increased Rates of Other Cancers in HIV

Case 1

• A 42 year old man with HIV (CD4 89) presents with fever, headache, fatigue and recurrent molluscum contagiosum.

• Blood cultures are taken, his molluscum lesions are treated with liquid nitrogen, he is given Tylenol for his fevers and goes home.

• He returns several days later more lethargic with a worsening headache, a temperature of 39 degrees C and more molluscum lesions.

Case 1

• Does he have any pulmonary symptoms?• What is his TB exposure and testing history?• Where has he lived?• What animal and environmental exposures does he

have?• What is his toxoplasmosis serology?• Has he had other infections in the past?• Tell me more about these skin lesions. Can I see

them?

What questions do you have regarding his history and physical exam?

Case 1

Mandell, Atlas of Infectious Diseases

Case 1

• Brain CT is negative• CSF analysis: opening pressure is 300 mm, WBC

0, protein 60, glucose 30, CRAG is negative, VDRL is negative, PCR for CMV, VZV, HSV and EBV are negative

What diagnostic testing do you want?

Case 1

• Cryptococcal meningitis• Bacterial meningitis (S. pneumoniae, H. influenza,

N. meningitidis, L. monocytogenes)• Tuberculous meningitis• Other chronic meningitides (histoplamosis,

blastomycosis, etc)• Viral meningo-encephalitis (e.g., HSV,

enteroviruses, other herpes viruses, rabies

Does he have meningitis?What is your differential diagnosis?

Case 1

What test do you want next?


Case 1

Silver stain of CSF

Narrow base

capsule


Case 1

Antigen excess (the prozone phenomenon)

Why was the CSF CRAG negative?

Case 1

• Initial therapy; AmphoB (0.7 mg/kg/d) with or without 5-FC for 2 weeks

• Followed by fluconazole at 400 mg/day for 10 weeks and then maintenance therapy with fluconazole at 200 mg/day.

• Relapse without suppressive therapy (or HAART) is 50 to 60%

(Van der Horst, NEJM, 1997)(Saag, CID, 2000)

How are you going to treat him?

Case 1

• High pressure associated with more symptoms (HA, meningismus, cranial nerve deficits) and higher antigen titers.

• Pressure > 350 is associated with early (first week) death

• Most experts recommend serial large volume spinal taps or spinal drains for patients with elevated CSF pressures

(Graybill, CID, 2000)

Anything else?

Case 1

• Cryptococcal antigen for monitoring therapy:• Serum; No: no correlation between titer and

outcome• CSF; Yes: unchanged or rising titer is associated

with failure and relapse.

• High dose steroids associated with increased mortality

(Powderly, CID, 1994)

How will you follow him?

Case 1

When should you provide HAART?

Timing of HAART

#142: Immediate Vs Delayed ART in Setting of Acute OI, Zolopa, Powderly, et.al. (ACTG 5164)

• Randomized study of ARV given within 14 days of Rx for OI Vs delayed (at least 4 wks)

• Patients with TB excluded• Primary endpoint: 48 week combination of 3 categorical

variables – 1. Death or alive with new AIDS diagnosis – 2. Alive with HIV RNA > 50 and no new AIDS diagnosis– 3. Alive with HIV RNA < 50 and no new AIDS diagnosis

Timing of HAART

#142: Immediate Vs Delayed ART in Setting of Acute OI, Zolopa, Powderly, et.al. (ACTG 5164)

• Patients (N=282)– Median age 38– Median CD4 = 29 and log10 HIV RNA level = 5.07– OIs

• PCP 63%• Cryptococcal meningitis 13%• Pneumonia 10%

– Median time to starting ART 12 Vs 45 days

05

101520253035404550

Death orNew OI

VL > 50 VL < 50

Immediate

Delayed

Timing of HAART

• No significant difference between immediate Vs delayed for the composite endpoint

• Immediate arm had fewer deaths/new AIDS diagnosis

• Immediate arm had longer time to death/new AIDS diagnosis (HR 0.53)

P=0.035

ACTG 5164: Results

Early Vs Delayed HAART in Patients with Cryptococcal Meningitis in Africa

(Macadzange,CROI,2009,Abs 38cLB)

• Open Label RCT

• Patients: Adults with HIV and Cryto meningitis (CSF CrAg or India ink positive)

• All received Fluconazole 800 mg PO once daily x 10 wks + aggressive pressure management

• Followed by maintenance fluconazole 200 mg

• Intervention: d4T, 3TC, NVP

– EARLY: Immediate start with initial fluconazole

– DELAYED: Start after initial 10 wks of fluconazole

• Primary Outcome: Mortality after 2 years



TOTAL: 50 patientsOverall 2-yr Mortality: 62%

EARLY 27 patients

Median Survival: 35 days*

2-yr Mortality: 87%**

DELAYED23 patients

Median Survival: 274 days

2-yr Mortality: 37%

*Comparison of median survival, p=0.03**Comparison of 2-yr Mortality, p=0.002



All but 2 deathsdue to Cryptococcus

Other 2 deaths ascribed to TB-IRIS

Baseline CD4 cells similarin those who died in each group

Case 2

• A 38 yo South African male presents with a 10 kg weight loss, 10 weeks of cough and intermittent fever. He has no past medical history.

• On exam he is thin, T 38.8 C, BP 100/70, HR 104, RR 20. He has prominent cervical adenopathy, oral thrush and course breath sounds over his R upper and mid lung zones.

Case 2

Initial CXR for Case 2

• What diagnostic tests do you want?• “HIV test is + and Sputum smear stains 3+ for AFB”

Case 2

• He is admitted to a hospital ward with similar patients and started on “RIPE” therapy.

• After a week his constitutional symptoms improve. His CD4 T-cell count measures 15 cells/uL.

• Should he be offered HAART? – If so, when should HAART be started?

– Are there TB and HIV drug interactions of concern?

Immune Reconstitution Syndrome

• TB-associated IRS in South Africa– 160 patients receiving Rx for

TB at the time HAART initiated

– Median CD4 68 – IRS in 12% overall, 32% in

those who started HAART within 2 months of TB Rx

– MV analysis: IRS risks• Low CD4• Early HAART – OR for

starting HAART < 30 days = 69.5

– 2 IRS deaths (both had disseminated TB

TB-IRS and CD4 and HAART

(Lawn, AIDS 2007;21:335-41)

SAPiT(Karim,CROI,2009,Abs36a)

• Open-label RCT• Patients

– Smear positive and on standard TB tx regimen– HIV positive with CD4 cell count < 500

• ART: ddI + 3TC + EFV once daily with TB DOT

• Endpoints– Primary: all cause mortality– Secondary: Tolerability, toxicity, viral load, CD4

count, TB outcomes and IRIS


Study Arms• Integrated TB-HIV treatment

1. ART initiated as soon as possible during the intensive phase of TB tx (first 8 weeks)

2. ART initiated after the intensive phase of TB tx

• Sequential – ART initiated after TB tx completed


Integrated Sequential

Initiated ART (n) 358 132

Completed (n) 94 (22%) 38 (18%)

Mortality (rate per 100 person-yrs)

5.2 12.1 HR 0.44(CI 0.2-0.8, p=0.003)

WHO/DHHS: Treatment

Start TB therapyHAART as soon as TB Rx tolerated (b/n 2-8 wks)Some experts would wait until 8 weeks (avoid IRIS)

Start TB therapyHAART after intensive phase of TB Rx(HAART earlier if severely immunocompromised)

Start TB therapyMonitor CD4 count and start HAART when indicated

TB therapy Improving, no OIs HAART when TB Rxcomplete

CD4 not available

CD4 100-200

CD4 200-350

CD4 > 350

HIV-TB

Extrapulmonary TBPulmonary TB

Start TB therapy, start HAART in 2 weeksCD4 < 100

TB/HIV Co-infection: Principles of Treatment

• Treatment generally the same as in HIV- patients (4 drugs for 2 months and 2 drugs for 4 months)

• Sub-optimal response (culture + after 2 months) – give 9 months, skeletal TB – 6 to 9 months, CNS TB – 9 to 12 months

• If using regimens without INH or a rifamycin - duration should be 12 to 15 months

Principles of Treatment:Importance of Rifamycin

• Treatment with NON rifamycin-containing regimens is associated with:

• Higher relapse rates

• Higher mortality

Wallis, et al. (1996) Tuber Lung Dis 77:516-23Hawken, et al. (1993) Lancet 342:332-38Perriens, et al. (1991) AM Rev Resp Dis 144:750-55Korwnromp, et al. (2003) CID 37:101-12

Principles of Treatment

• Be wary of drug interactions between the rifamycins and HIV medications

• Do not use TB treatment regimens that are dosed weekly (e.g. INH-rifapentine) or even twice weekly in patients with CD4 counts < 100

• Consider measuring drugs levels if there is concern for malabsorption or increased elimination of TB therapies


Drug Interactions: The P450 system

• Isoform CYP 3A is affected and/or involved in the metabolism of rifamycins, NNRTI and PIs

• Rifamycins: Induce CYP 3A– Rifampin > rifapentine > rifabutin

– Rifampin is not metabolized by CYP 3A (level not affected by other drugs that influence CYP 3A)

– Rifabutin is metabolized by CYP 3A (level is affected by other drugs that also affect CYP 3A)


• If using rifampin - avoid PI-based HAART - use NNRTIs (EFV preferred over NVP)

• If using rifabutin - can use PIs or NNRTI - but will have to dose adjust the rifabutin in most cases


Web site for more complete table showing dosages:http://www.cdc.gov/tb/TB_HIV_Drugs/Table1.htmAlso tables 2 and 3

http://www.cdc.gov/tb/TB_HIV_Drugs/Table1.htm

Case 2

…back to the case• 10 days into his TB therapy he is started on

HAART.• 3 weeks later his fever and cough return

Case 2

Follow up CXR for Case 2

• What are you worried about and what are you going to do?

XDR TB

# 143: Exogenous Re-infection with MDR and XDR TB Among TB/HIV Infected Patients in Rural South Africa,

Andrews, et.al.

• Case control study of patient with pulmonary TB at Church of Scotland Hospital, South Africa from 2005-06

• N=170; 43 had baseline and follow-up cultures; 23 developed MDR or XDR TB

XDR TB# 143: Exogenous Re-infection with MDR and XDR TB Among

TB/HIV Infected Patients in Rural South Africa, Andrews, et.al.

170 patients with TB

43 had both initial and follow up cultures done

23 developed MDR or XDR TB

17 had paired spoligotypes performed

17/17 pairs were NOT matched

Treatment and Outcome

(Raviglione, NEJM 2007;356:656-59)

MDR and XDR TB

http://content.nejm.org/content/vol356/issue7/images/large/02f1.jpeg

Treatment and Outcome

• XDR TB– Report of 53 cases in rural

South Africa– 55% had never been treated

for TB– 67% had recently been

hospitalized– 44 (100%)/44 tested for

HIV were + (median CD4 63)

– 52 (98%)/53 died, median survival of 16 days

• 49 cases in USA: HIV+: 74% (1993-99) Vs 10% (2000-06)

Survival

(Gandhi, Lancet, 2006; 368: 1575-80)(MMWR, 2007; 56(11): 250-53)

Case 3

• A 47 year old extremely sexually active Cuban male was brought to the ED by one of his girlfriends with confusion. He denied all symptoms and denied being HIV infected

• Exam revealed a temperature of 38.3, HR 99, BP 110/70, RR 12. He had thrush and slight R facial droop, mild R UE weakness and an unsteady gait

• CD4 count was 9, HIVRNA is > 1 million . He tested negative for antibodies to toxoplasmosis.

• What other tests results would you like?

Case 3

(aidscience.org)

Case 3

CSF Analysis

• Cell count: 15 wbc (all lymphocytes), 0 rbc

• Glucose: 50 (serum 80)

• Protein: 30

• VDRL: negative

• CRAG: negative

• Fungal, Gram’s and AFB stains: negative

• PCR for HSV, CMV, VZV: negative

• PCR for EBV: positive

Case 3

• Toxoplasmosis• Primary CNS lymphoma• Tuberculomas• Cryptococcomas and other dimorphic fungi (histo, cocci, blasto)• Nocardia• Syphilis• Bacterial brain abscesses• Metastatic tumors• CVA with edema

Differential Diagnosis?

Case 3• PCNSL occurs in up to 2% of AIDS patients

• Thallium SPECT and PET scans are useful for differentiating toxoplasmosis from PCNSL. Sensitivity > 90%, specificity? (false + with tuberculomas, cryptococcomas and other omas)

• PCR for EBV in CSF: sensitivity 85 to 97%, specificity much lower, PPV 29-50% (Corcoran, J Clin Virol, 2008;42,433-36)

• Combination of PCR and SPECT scans may make the diagnosis and obviate the need for biopsy - No

Case 3

Mass lesion(s) on CT or MRI

Toxoplasma serology?

Multiple or Single lesions?

Empiric Toxoplasmatherapy

Positive

Biopsy

CSF EBV PCR

Treat for lymphoma?*

Continue Toxoplasma Rx

Improvement in 2 wks

Negative

Multiple Single

No improvementin 2 wks

Negative Positive

*Use PET or SPECT

Case 3

(aidscience.org)

Final Answer: Sometimes its both

Toxoplasma gondii

• Organism– Toxoplasma gondii, a protozoa

• Epidemiology and route of infection– By age 50, sero-prevalence rate is 15% in USA

compared with 90 to 100% in France and developing nations

– Ingestion of oocysts or tissue cysts leads to the release of organisms which mature into tachyzoites, disseminate and then persist in the CNS or other tissues

– Immunosuppression allows for the development of trophozoites from the tissue cysts leading to disease.

Toxoplasma gondii

• Clinical presentation/syndrome– CD4 < 100. Encephalitis; fever, mental status changes, headache,

seizures and focal neurological signs.

• Diagnosis– Serology (ELISA) is positive is over 95% of patients? (reported range 22-

95)

– MRI or CT shows multiple enhancing lesions in the grey-white matter junction, white matter or basal ganglia

– Definitive diagnosis requires brain biopsy; a presumptive diagnosis can be made given a characteristic presentation and response to anti-Toxoplasma therapy.

Toxoplasma gondii

Treatment• Pyrimethamine plus sulfadiazine plus leukovorin or

• Pyrimethamine plus clindamycin plus leukovorin or

• High dose TMP/SMX (Torre, AAC;42,1346-9)

• Other regimens active against Toxoplasma– Atovaquone plus pyrimethamine plus leucovorin

– Atovaquone plus sulfadiazine

– Azithromycin plus pyrimethamine

• A 24 year old male was flown down from Alaska for fever, weight loss and fatigue lasting 6 weeks. He is HIV infected with a CD4 of 70 and on no anti-retroviral therapy

• PMH: thrush• Born in southern Illinois, had lived in Alaska for last 6

years. Worked as a fisherman, former IVDU• Exam revealed a cachectic male, T of 40, with a papular

skin rash, a tender ulcer on his tongue, organomegaly, WBC 1.5, Hct 21, Plts 66,000, CXR showed mild diffuse infiltrates, calcified hilar nodes and calcifications in LUQ

Case 4

Case 4


Case 4

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

(www.aids-images.ch)

Other representative images

Differential diagnosis?

Diagnostic tests?

Case 4

Case 4

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

(www.accessmedicine.com)

Buffy Coat Preparation

Intracellular yeast forms

Histoplasmosis• Organism

– Histoplasma capsulatum, a dimorphic fungus, grows in mycelial phase in the environment and as a yeast in vivo.

• Epidemiology– Endemic to central North America (Mississippi and

Ohio River valleys), Latin America, The Caribbean and other selected tropical areas

– Fungal spores are contained in soil enriched with bird/bat droppings (droppings enhance growth and accelerate sporulation)

– 2 to 5% of HIV+ patients living in endemic regions develop histoplasmosis

Histoplasmosis

Mold phase Yeast phase, liver biopsy

yeastmacroconidida


Histoplasmosis

Pathogenesis• Spores are inhaled and taken up my lung macrophages,

grow as intracellular yeasts and disseminate within 2 weeks leading to

• Controlled infection (most common in HIV negative persons); patient left with calcified granuloma (lung, spleen)

• Uncontrolled infection (progressive disease) in those with T-cell dysfunction

• Progressive pulmonary disease in those with COPD• Chronic histoplasmosis, due to an unusual inflammatory or

fibrotic response to the fungus: rheumatologic syndromes, pericarditis, mediastinal inflammation or fibrosis

Histoplasmosis

HIV+ patients• Illness severity related to intensity of

exposure and immunity of host• Most symptomatic HIV infected patients

have CD4 < 150 (90%)• Disease usually due to acute infection but

may result from reactivation in some cases

Histoplasmosis

Syndromes in HIV infected patients• Disseminated infection (95%) – fever, weight loss, anemia,

organomegaly

• Pneumonitis (50%) – most often presents with a diffuse reticular pattern on CXR

• CNS involvement (5-20%) – chronic meningitis, focal brain lesions

• Shock and ARDS 10- 20%

• Other sites: lymphnodes, mucosal lesions, gastrointestinal, ocular

Histoplasmosis

Diagnosis• Histoplasma antigen (false + in blastomycosis,

coccidioidomycosis, paracoccidioidomycosis)– Urine 95% sensitive – Serum 86%– CSF 70%– Alveolar lavage fluid 67%

• Culture; sensitivity 70 to 90%; takes 1 to 6 weeks to grow• Fungal stain of tissue; sensitivity up to 70%, buffy coat

stain positive in up to 45%

Histoplasmosis

Treatment• Prophylaxis - consider in “high risk persons” with CD4 < 150

(intraconazole 200 mg/day)• Mild disease: Itraconazole• Moderate to severe disease: Liposomal AmB (superior to AMB)

for .5 to 2 weeks followed by itraconazole for 10 weeks or high dose fluconazole

• Maintenance: Itraconazole > fluconazole (more relapses with fluconazole)

• CNS disease: Ampho B followed by fluconazole• Measure intraconazole levels at least once (> 1ug/mL)• Safe to discontinue secondary prophylaxis in individuals who have

been treated for a year, are on HAART with CD4 > 150, and have histo serum Ag < 2

Case 5

• A 46 yo Native American female with advanced HIV (CD4 44), not on HAART presents with incoordination of her R hand, an unsteady gait and slurred speech

• Exam reveals and thin woman, alert and oriented, BP 90/60, HR 90, RR12, temperature 37. She has a slight R facial droop, R hand weakness and dysmetria and an unsteady gait due to mild R leg weakness

Case 5

• Differential diagnosis and diagnostic tests?

PML and HIV

PML• Caused by JC virus (a polyoma virus)• 85% of adults have serologic evidence for

infection• Most are asymptomatically infected as children• Latent in kidney, traffics in lymphocytes and may

be latent in brain

PML and HIV

Clinically• Typically presents with focal CNS signs.

Preference for– Occipital lobes (hemianopia)– Frontal and parietal lobes (hemiparesis)– Cerebellum (ataxia and dysmetria)

• Seizure in 20%• Insidious progression over weeks to months

PML and HIV

Clinically• PML IRIS

– Onset after HAART– Typical clinical presentation– Atypical MR - edema and mass effect, significant

enhancement– Less JCV by PCR– May have better outcome

PML and HIV

Diagnosis• Typical MR findings - patchy white matter lesions

(hyperintense on T2 and flair), 10-15% enhance with gadoliium

• CSF JCV PCR positive in 70 - 90%• Brian biopsy

PML and HIV

Treatment• HAART

– > 60% response rate (20-30% improve)– Worse outcomes for those with CD4 < 150

• Serotonergic receptor 5HT2a may be used by JCV: anecdotal reports of 5HT2a binding agents having benefits (olanzapine, mirtazapine, respiradone)

• Steroids for PML IRIS

Summary

• Opportunistic infections are predictable based on a patients immune status and environment

• Disseminated and atypical presentations are the rule with extreme immune suppression

• Prophylaxis against certain OIs is indicated if the OI is common and the prophylaxis is affordable, effective and well tolerated

• HAART alone is treatment enough for certain OIs and can eliminate the need for prophylaxis

• The timing of HAART relative to OI therapy is controversial but should probably be early…..except with cryptococcus and watch out for IRIS!

hiv-associated opportunistic infections 2009

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