Key Fact #1: CD4 count TB Recurrent bacterial pneumonia, TB, HSV, - - PDF document

12/8/17 1 Opportunistic Infections and Immune Reconstitution Inflammatory Syndrome

5 Things You Need To Know

Carina Marquez, MD, MPH Assistant Professor

University of California, San Francisco Division of HIV, ID, and Global Medicine Zuckerberg San Francisco General Hospital

Disclosures

• I have no disclosures to report

Key Fact #1: CD4 count correlates with risk of specific OIs in untreated HIV disease

CD4 count correlates with risk of specific OI’s in untreated HIV disease

100 200 300 400 500 600 700 800 >500 200-500 100-200 50-100 <50 PCP, PML, Histoplasmosis, MAC CMV, Primary CNS lymphoma Recurrent bacterial pneumonia, TB, HSV, VZV/Zoster, NHL, Kaposis Sarcoma,

• ropharyngeal candidiasis

Toxoplasmosis, Cryptococcosis Cryptopsoridiosis CD4 Count CD4 Count Category

Adapted from Bartlett JG, Galant JE, Pham PA. Medical Management of HIV. 2012

TB

12/8/17 2

44 y/o M with HIV (CD4 94, not on ARVs

• r prophylaxis) presents with 1 month of

progressive SOB, non-productive cough, fevers, night sweats, and weight loss.

• Exam: Afebrile, 90% RA. Diffuse

crackles, thrush, bilaterally and mild wheezing.

• Labs: WBC 8.3. LDH 386, BDG>500.
• ABG: 7.44/35/59 on RA

Case #1 Case #1: continued

• A. He should be started on empiric treatment for community

acquired pneumonia, TMP/SMX, and prednisone

• B. If this patient has a septra allergy you should consider septra

desensitization.

• C. Pneumocystis carinii causes pneumonia in rats.
• D. The specificity of beta d-glucan with PCP is 92%

ARS: Which is the following is NOT true

• Subacute presentation of cough: often present with dry cough, DOE
• CD4 <200
• >90% of cases occur with CD4<200
• CXR and chest imaging-
• Diffuse bilateral symmetric infiltrates, seen in 60% of cases
• HRCT for ground glass (Sensitivity ~100%, specificity 89%)
• Pneumothroax common, 35% in cystic PCP
• Lymphadenopathy, cavitations and effusion are NOT common
• Early presentation
• Hypoxemia with normal CXR (possible in early disease)
• Desaturation with exertion

When to suspect PCP

12/8/17 3

• No culture system for P. jirovecii
• Sensitivity of stained respiratory secretions
• Induced sputum: <50-90%
• BAL: 95-100%
• Elevated LDH
• Sensitivity 83-100%, specificity 25-85%
• Beta D Glucan
• (1→3)-β-D-glucan is a component of the cell wall of most fungi (including P jirovecii)
• Sensitivity 92%, specificity 65% for PCP using a cutoff of 80 pg/ml
• Other fungal causes of positive BDG: candidiasis, histoplasmosis, cryptococcus
• Most useful if negative

Grover, Clin Invest Med 1992. Sax, CID 2011.

PCP: Laboratory Diagnostics

• TMP-SMX is first-line therapy
• Dosing:
• TMP/SMX (TMP 15–20 mg/kg and SMX 75-100mg)/kg/day divided q6h-q8h
• Use IV TMP/SMX for moderate to severe disease and may switch to PO after clinical improvement
• Patients who get PCP despite TMP-SMX prophylaxis still respond to standard dosing
• Desensitization protocols available for patients with allergy
• Steroids within 72 hours in severe disease: RA PaO2<70 mm Hg or A-a gradient>35 mm Hg
• Prednisone 40 mg bid x 5d then
• Prednisone 40 mg qd x 5d then
• Prednisone 20 mg qd x 11d
• Duration of therapy: 21 days then start secondary prophylaxis
• Adverse effects are common in HIV+ patients
• Rash, fever, leukopenia, thrombocytopenia, azotemia, hepatitis, hyperkalemia
• Try to “treat through” common (non-life threatening) reactions if possible

DHHS OI Guidelines 2017

PCP Treatment

• Moderate to severe disease (PaO2<70, A-a grad >35):
• Pentamidine (IV) 4 mg/kg IV daily
• Historically preferred as the 2nd line agent for severe disease (A-a gradient > 45) because of

more efficacy data

• Serious side effects (irreversible renal and pancreatic islet cell toxcity, orthostatic hypotension,

profound hypoglycemia, cytopenias)

• Clindamycin (IV: 600mg Q6h or 900mg Q8h. PO: 450mg Q8h) + Primaquine (30mg

PO daily; check G6PD)

• Mild disease (PaO2 >70, A-a grad<35):
• Clindamycin (450 mg q6hr or 600mg q8hr) + primaquine 30mg (base) PO daily
• Atovaquone 750mg PO BID with food
• Dapsone 100mg PO daily + TMP 15mg/kg/day PO [3 divided doses]

DHHS OI Guidelines 2017

Alternative Rx for Failure or Toxicity

• Started on empiric CTX/doxy + TMP-SMX/prednisone.
• Could not get induced sputum.
• BAL:
• AFB smear and cx neg
• Bacterial: oral flora
• PCP positive
• After BAL returned: CTX/doxy stopped, TMP-SMX/prednisone continued.

Back to Case 1

12/8/17 4

37 y/o man with HIV (CD4 28) presents with fever, AMS, and seizure. ARS: What do you recommend?

• A. Brain biopsy
• B. Start empiric toxo therapy
• C. Start RIPE to treat empirically for TB

Case #2

Long Differential

Skiest DJ Focal Neurologic Disease In patients with acquired immunodeficiency syndrome . CID 2002.; Chamie Semin Neurol. 2014

Selected Ddx of Space Occupying Lesions in HIV

Short Differential

• Toxoplasma gondii
• Primary CNS lymphoma

Bacterial Pyogenic abscess Nocardia Rhodacoccus Tuberculoma/NTM Syphilis Fungal Cryptococcoma Histoplasma Parasitic Toxoplasma gondii Chagas disease/chagoma Malignancy Primary CNS lymphoma

• Occurs at CD4<100, but highest risk if CD<50
• Almost exclusively due to reactivation of latent infection
• Transmission occurs by ingesting oocysts excreted in cat feces (in cat

litter or soil) or by ingesting undercooked meat (pork and lamb) or raw shellfish containing tissue cysts

• Subacute presentation over several weeks: HA, fever, behavioral

changes, confusion, hemiparesis, seizures, ataxia, CN palsies, diffuse encephalitis.

Skiest, CID 2002.

CNS Toxoplasmosis: Epi and Clinical

• Lesions are most commonly located in the parietal or

frontal lobes and at the corticomedullary junction, basal ganglia, thalamus, and pituitary gland

• Lesions can be single or multiple:
• Classic finding is ≥2 ring-enhancing lesions with

surrounding edema

• But up to 27%–43% of patients have a single lesion
• In rare cases patients can have diffuse encephalitis

with no focal lesions

Skiest, CID 2002.

CNS Toxoplasmosis: Imaging

Imaging findings for 2 other patients with toxoplasmosis

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• Serum toxo IgG: if negative then virtually excludes infection because

<3%–6% of patients with TE have negative IgG

• CSF studies:
• Chemistries may be normal or show mild increase in protein, lymphocytic

pleocytosis, low glucose

• Toxo CSF PCR: sensitivity only 50% although specificity 96-100%. A negative

test does not rule out disease.

• It is very difficult to distinguish between Toxo and primary CNS

lymphoma based on clinical findings alone

Skiest, CID 2002.

CNS Toxoplasmosis: Laboratory Diagnosis

• Usually treat empirically based on positive serum IgG
• Follow MRI in 2 weeks
• Should see radiographic improvement within 2 weeks – if not then consider alternative

diagnosis, pursue biopsy to rule out other causes

• First choice regimen: Pyrimethamine plus sulfadiazine plus leucovorin x 6 weeks
• Then secondary ppx: pyrimethamine plus sulfadiazine plus leucovorin
• Pyrimethamine: rash, nausea, and bone marrow suppression (can reverse by increasing

leucovorin dose)

• Sulfadiazine: rash, fever, leukopenia, hepatitis, nausea, vomiting, diarrhea, and crystalluria

(encourage hydration)

• Alternative regimen (for toxicity or clinical failure)
• Pyrimethamine plus clindamycin
• Pyrimethamine free: TMP/SMX alone or Atovaquone+/-sulfadiazine
• Other possible regimens listed in CDC guidelines, especially if need IV options
• Avoid steroids (if possible) if treating empirically because this will treat lymphoma as well

DHHS OI Guidelines 2017

CNS Toxoplamsosis: Treatment

• Occurs usually at CD4<50, subacute

presentation

• Imaging:
• Lesions can be single or multifocal, or often single
• Usually enhance homogenously, but can also be

rim-enhancing

• Characteristic finding is to be next to CSF (eg

periventricular, meningeal, subependymal)

• CSF findings:
• Mild elevated protein and pleocytosis
• EBV PCR: sensitivity >80%, specificity 94-100%

Skiest, CID 2002.

Primary CNS Lymphoma

36 yo M with AIDS off ART (CD4 10, VL 314K) who presented for altered mental status, found to have CNS lymphoma. CSF: EBV DNA +, Toxo IgG neg Serum: Toxo IgG neg

Case #3

• CC: 51 M p/w shortness of breath
• HPI:
• Dyspnea & reduced exercise tolerance x 1 mo
• Sweats, fevers, 10 lb weight loss x 1-2 mo

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Labs / Studies at presentation

• HIV Antibody (+), CD4 39
• Sputum AFB smears (-) x 3

Serum CrAg (+) 1:32,768 LP: OP 28 cm, WBC 2 (N0, L93, M7), RBC 2, Glu 60, Prot 42 CSF CrAg 1:128, CSF cx C neoformans Induced sputum + BAL C neoformans Blood cx C neoformans

• Most cases occur when CD4<100
• Clinical:
• Presents as subacute meningitis or meningoencephalitis
• Can also see encephalopathic signs/sx due to elevated ICP
• Diagnosis:
• Serum and CSF CrAg are almost always positive
• CSF studies: lymphocytic pleocytosis or no cells, mildly elevated protein, glucose

normal to low, elevated OP

• Low CSF WBC portends a poorer prognosis

DHHS OI Guidelines 2016

Cryptococcus Meningitis

• Induction (14 days):
• Amphotericin 0.7 mg/kg/d or liposomal amphotericin 3-4 mg/kg/d plus
• Flucytosine (5-FC) 100mg/kg/d in 4 divided doses
• Consolidation therapy (8 weeks):
• Fluconazole 400mg (6mg/kg) PO daily
• Chronic maintenance therapy:
• Fluconazole 200mg PO daily
• Consider stopping when CD4>200 and VL suppressed for 6 mo

DHHS OI Guidelines 2016; IDSA Guidelines, CID 2010.

Cryptococcal Meningitis: Treatment

• Elevated ICP is the leading cause of death from CM in the first 2 wks

after diagnosis

• Management strategy:
• Measure OP at diagnosis (normal is <20 cm H2O)
• If OP is elevated: daily LPs to remove volume (~20-30cc) that at least

decreases OP 50%.

• Aim for at least 1-2 days of stable pressures
• If symptoms persist or can’t do daily LPs, then consider EVD/lumbar drain
• VP shunt can be done in the setting of anti-fungals if other measures fail

DHHS OI Guidelines 2016. IDSA Guidelines, CID 2010.

Cryptococcal Meningitis: Management of Elevated ICP

12/8/17 7

ARS: when do you start antiretroviral therapy?

• A. Within 2 weeks
• B. 5 weeks from start of anti-fungal therapy
• C. 8 weeks from start of anti-fungal therapy

Case #3 continued

Advantages

• Sometimes ARVs are the best

treatment for the OI

• PML, cryptosporidiosis, KS,

microsporidiosis

• Prevention of a second OI
• Restore pathogen-specific

immunity (more rapid clearance

• f OI)
• Slow HIV progression

Disadvantages

• Risk of IRIS (especially if occurs

in CNS

Starting ARVs during an Acute OI

ART Timing in Cryptococcal Meningitis COAT Study, 2013 (trial halted)

Cryptococcal Optimal ART Timing (COAT) Study RCT (UG+S.Af.), 2013

(Boulware, CROI Atlanta, 3/6/13)

Early ART (n=88) Later ART (n=89) Ampho/Fluc800 2w, then Fluc800 until CSF sterile, then Fluc 400 x 8wks PLAN: <48h à 7d (5-10) PLAN: >4 wks à 32d (28-36) Median CD4+ count 19/uL (9-69) 28/uL (11-76) Death CSF WBC < 5 cells/mm3 45% death by 6 mo. HR 2.21 (0.91-5.34) 30% death by 6 mo. ref p=0.03 p=0.008 CCM-IRIS (definite/probable/possible) 16.2% 10.1% p=0.347

• DHHS 2017 Guidelines: delay ART 2-10 weeks.
• Usually delay after 4 -5weeks.
• Patients with <5 CSF WBC have a higher risk of mortality and have

more to gain with delayed ART.

Summary Cryptococcal Meningitis

12/8/17 8

Patients with Cryptococcal Meningitis may not have a headache….

47 yo M with CD4 10, VL 1 million p/w fever x

• months. No headache and

normal neuro exam. Serum CrAg 1:16860 CSF CrAg 1:8000, culture. Cryptococcal neoformans Dx: Cryptococcoma with cryptococcal meningitis

Case #4

• 46 year old man with HIV (CD4 201, VL- 120K),

admitted for cough, fever, and weight loss

• Exposed 6 months ago to someone “coughing up

blood”, and had a newly positive quantiferon 3 months ago. Did not receive LTBI treatment as patient was loss to follow up, after he did his CXR.

• CXR shows left upper lobe infiltrate
• What are your next steps for assessing for TB?

Which statement is false?

• A. Sensitivity for Gene Xpert MTB/RIF is >95% in HIV-infected patients with

smear positive disease

• B. Sensitivity and specificity for Gene Xpert MTB/RIF is similar between HIV-

uninfected and HIV-infected with smear negative/culture positive disease

• C. If this patient has TB and CD4 <100, he would benefit from steroids to

prevent TB-IRIS.

• D. If this patient had TB, I would start ART after 8 weeks of starting TB

therapy

TB Diagnostics

• Xpert MTB/RIF: 2 hour molecular test for M.TB diagnosis

and rifampin resistance

• Point of care test
• More sensitive than AFB smear1
• Screen for MDR and XDRTB
• 1. Lawn, Lancet ID, 2. Alland CROI 2015;
• TB Culture remains the gold standard
• TB can be smear negative, rely on your clinical suspicion to
• initiate empiric therapy if needed

12/8/17 9

Xpert MTB/RIF is great for ruling out smear positive disease in both HIV-infected and uninfected persons

Luetkemeyer CID 2016:62 (1 May)

HIV-infected Sensitivity % (Xpert +/Culture+) HIV-uninfected Sensitivity% (Xpert +/Culture +) p Overall 74% 87% 0.02 AFB+/TB culture + 100% (39/39) 98% (90/92) >0.5 AFB-/TB culture + 51% (25/48) 58% (21/36) >0.5

*Overall specificity 98.9%, in the US 99%

New New Ho Horizo zons: : Xpe Xpert rt Ul Ultra ra, , impro proved d sens nsitivity for for smear ar negat ative ive dis iseas ase!

• Pulmonary TB- Improved sensitivity compared to Xpert in smear negative

TB disease and fewer samples with false positive RIF resistance. Lower limit

• f detection- 16 bacterial CFU (compared to 114)
• Game Changer for TB Meningitis- Prospective study of 129 patients with

suspected meningitis in Uganda, Ultra detected more cases then Xpert and culture. 2

• Sensitivity (Composite definition): Ultra 95%, Xpert 45%, Culture 45%
• Ultra identified 21 cases not identified by culture

Xpert Ultra Xpert MTB/RIF Smear Negative Culture Positive 80% 66%

SENSITIVITY ULTRA vs. XPERT MTB/RIF1

• 1. Chakravorty MBio 2017, 2. Bahr Lancet ID 2017

Case #4 Continued

• Pt is diagnosed with TB by Gene Xpert with culture pending
• Started on treatment for TB with isoniazid, rifampin, ethambutol and

pyrazinamide

• When should you start ART?

Current Guidelines for ART start in pulmonary and extra pulmonary TB (excluding meningitis)

• WHO, American Thoracic Society, and DHHS guidelines all

recommend:

• Initiation of ART within 2 weeks for CD4 count <50
• Early ART educed risk of mortality and AIDS defining illness in 3 RCTs

by 34-68%

• Initiation of ART within 8 weeks for CD4 >50
• Early ART reduced the risk of mortality and AIDS defining illnesses by

11-34% in 3 RCTs.

Blanc NEJM 2011, Havlir NEJM 2011, Abdool Karim NEJM 2011

12/8/17 10

• CMV retinitis: We wait 14 days. Limited data.
• Inflammatory CNS lesion: For those who have evidence of brain

edema, mass effect, or neurologic deficit we recommend waiting at least 14 days of OI antimicrobial therapy. Data limited.

• Cryptococcal Meningitis
• TB meningitis

When NOT to immediately start ART in the setting

• f an OI: the Zuckerberg San Francisco General

Hospital Experience

W86 clinical guidelines: http://hivinsite.ucsf.edu/InSite?page=md-ward86-art-oi

Key Fact #2: OIs can be prevented with ART and primary and secondary prophylaxis

OI Indications for Primary ppx Regimen of Choice Alternative Regimens When to stop ppx

PCP

CD4<200 or CD4<12% or h/o thrush or AIDS defining illness TMP-SMX 1 DS daily or 1 SS

• TMP-SMX 1 SS daily or 1 DS tiw
• Dapsone (check G6PD)
• Dapsone + pyrimethamine + leucovorin
• Aerosolized pentamidine
• Atovaquone

CD4>200 for >3 mo, HIV RNA <40

Toxoplasma gondii

Toxo IgG positive AND CD4<100 TMP-SMX 1 DS daily

• TMP-SMX 1 DS tiw
• Dapsone + pyrimethamine + leucovorin
• Atovaquone 1500 mg daily

CD4>200 for >3 mo, HIV RNA<40

MAC

CD4<50 and no active MAC *send AFB Bcx first Azithro 1200mg qweek

• Azithro 600mg po twice/week
• Rifabutin 300mg po daily (watch for drug

interactions, r/o TB) CD4>100 for >3 mo, HIV RNA<40

DHHS OI Guidelines 2017

Primary Prophylaxis of OIs: The Basics TB Prevention

• Screen
• Risk of progression to TB disease 10x greater in HIV+
• CDC recommends testing for latent TB after HIV diagnosis (quantiferon and

tuberculin skin test), repeat 1 year after ART start, then annually if negative & at risk for TB

• Prevent TB, Treat LTBI
• Early ART and IPT independently decrease mortality among PLWHA*
• Treat with TB preventive therapy if

a) QFT or TST newly positive or b) close contact to TB (even if already has been treated for LTBI or TB in the past)

• Perform symptom screen and CXR, and rule out active disease before treating LTBI.

*Temprano ARNS Study Group NEJM 2015; Badje Lancet Global Health 2017

12/8/17 11

LTBI/HIV Treatment Options

Resources:(1) https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf, (2)htttp://www.hivdruginteractions.org/.

• 1. Luetkemeyer CID 2013, 2.. Custodio et al EACS 2017 Abstract PS13/4, 3.Dooley et al. JAIDS 2013 4. Brooks CROI 2017 #409a

LTBI Regimen Common DDI with ART Comments Isoniazid x 9 mo +B6

• Can be used with ANY ART regimen

Therapy long

Rifampin x 4 mo

• Efavarinz: Can use, no dose adjustment needed1
• Dolutegravir: Increase to 50mg PO BID
• Cannot use with a PI
• TAF: New PK data suggests adequate levels with BID dosing2
• Cobicistat- limited data, not recommended
• Rilpivirine- contraindicated

Check for DDI

Rifabutin x 4 mo

• DTG: Can use 50mg daily3
• PI: Can use with PI, rifabutin dose= 150mg daily
• Cobicistat- limited data, not recommended
• Rilpivirine: Limited data, 2017 package insert states increase to 50mg daily

Check for DDI, Less data for LTBI treatment with rifabutin

Isoniaizid + Rifapentine weekly x 3 mo

• Only efavirenz or raltegravir based regimens (in combination with either

abacavir/lamivudine [ABC/3TC] or tenofovir disoproxil fumarate/emtricitabine [TDF/FTC])

• PK study on dolutegravir stopped early due toxicity4

Limited options with ART Check for DDI

Key Fact #3. Ockham’s Razor does not apply to OIs and AIDS

40 yo M, with HIV (last CD4 420 and undetectable VL, one and half years ago, loss to follow-up) presents to urgent care with cachexia, fever, diarrhea (10x a day), and abdominal pain

• PMH:
• HIV diagnosed 2 years ago, CD4 380 VL 80K.
• Started on truvada and dolutegravir, suppressed for 6 months, but then lost to follow up
• SH: immigrated from Mexico 20 years ago, marginally housed
• Labs: Hgb 7, CD4 48 (6%), VL 200K, nl LFTs and Cr 1.0

Case #5

Abdominal CT Chest CT

Imaging

Numerous pulmonary nodules UL and RML- largest 1.8cm. Bulky mesenteric, retroperitoneal, and portacaval

• lymphadenopathy. Non-dilated fluid filled loops of small

bowel and colon suggestive of ileus.

12/8/17 12

Sy Syndromic Diff fferential Can Help Predict Pathogens in Patients wi with a a CD CD4<50

Short DDx: AIDS + Fever + Wasting + LAD Disseminated MAC Tuberculosis Disseminated Fungal (Crypto, Histo, Cocci) Malignancy

Short DDx: AIDS + Pulmonary Nodules Tuberculosis Kaposi's Sarcoma Fungal (Cryptococcus, Coccidioidomycosis) Lymphoma

Short DDx: AIDS+ Chronic Diarrhea Parasites (cryptosporidium, microsporidium) Bacterial (salmonella, shigella), mycobacterial (MAC colitis, TB ileitis) Viral: CMV colitis, Kaposi’s Sarcoma (HHV8) Fungal: histoplasmosis Other: HIV enteropathy.

• Stool cultures and O&P- giardia ag pos, entamoeba histolytica,

cryptosporidium.

• Serum CrAG-negative
• Urine histo Ag-negative

Case 4 (cont.)

Colonoscopy Colonoscopy Cytopathic changes consistent with CMV

Nucleomegally and Smudgy chromatin

12/8/17 13

Colonoscopy Granulomatous inflammation with AFB Lung Biopsy- Kaposi’s Sarcoma

Stains for HHV-8 H&E- spindle cells

Case 4-Final Diagnosis

• 1. Disseminated KS: Tongue, skin, colon, and lungs
• 2. CMV esophagitis and colitis
• 3. Disseminated MAC – MAC on LN and colon biopsies; blood cultures

grew MAC

When to suspect Mycobacterium Avium Complex

Clinical:

• Fever, weight loss, wasting, +/- diarrhea, +/- abdominal pain

Laboratory:

• CD4<50
• Elevated AlkPhos
• Often with anemia or pancytopenia due to bone marrow infiltration

Diagnostics:

• AFB Blood Cultures (important to draw prior to given azithromycin)
• Sensitivity 91% for 1 AFB blood cultures
• Sensitivity 98% for 2 AFB blood cultures
• CT abdomen often reveals hepatosplenomegally and intrabdominal

lymphadenopathy

• May need tissue biopsy

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Drug 1 Drug 2 +/- Drug 3 +/- Drug 4 Clarithro (more data) Or Azithro (better tolerated, less drug interactions)* Ethambutol Rifabutin Moxifloxacin Levofloxacin Ciprofloxacin Amikacin Streptomycin

Karakousis, Lancet ID 2004. CDC, MMWR 2013. *Dunne CID 2000 **Benson CID 2003

MAC Treatment: At Least 2 Drugs

• Consider a 3rd drug when:

v

High burden of disease

v

Not on ARVs

v

**mortality benefit with 3 drugs vs. 2 drugs, but pre HAART era

• Monitoring:
• Check AFB cx at 4-6 weeks
• Consider treatment failure ,if

no improvement in sx and still bacteremic after 4-8 wks

• Usually occurs when CD4<50
• Screening eye exams in patients

with CD4 <50 recommended

• CMV in AIDS manifests as (in
• rder of frequency):
• Retinitis: before HAART, 30-40%

developed this

• GI: colitis (5-10%), esophagitis (<5-

10%)

• Neuro: encephalitis,

polyradiculomyelopathy

• Pneumonitis: very rare, usually

bystander in BAL and not cause of pulmonary disease

CMV and AIDS

CMV retinitis-Image NIHhttp://www.nei.nih.gov/photo/eyedis/index.asp

Diagnostics

• CMV PCR not helpful, except for in

setting of CNS involvement

• Need tissue (aside from ocular

disease)

Key Fact #4: There is an increased risk of IRIS with CD4<50-100

5 weeks after starting ARVs, the patient was readmitted with new fever to 39.4, CT showed mild increase in size of mediastinal/intra- abdominal nodes. CD4 went from 46 -> 85, and VL 200 Kà 110 What’s on your ddx?

Case #5 continued

12/8/17 15

• Immune reconstitution inflammatory syndrome (IRIS)
• Adverse med effect
• Treatment failure (noncompliance, resistance, poor absorption of

meds)

• New OI, malignancy, autoimmune process

DDx: Worsening of OI After Starting ARVs ARS: Chose the statement that is FALSE

• A. NSAIDS can be used to treat mild IRIS
• B. Mortality of cryptococcus IRIS is over 20%
• C. This patient could have KS IRIS
• D. PCP IRIS is common
• Broadly defined as a syndrome of an exaggerated immune response

to antigens AFTER starting ARVs

• Timing: Recent initiation of ARVs (usually within 3 mo) with decrease

in VL and/or increase in CD4

• Usually infections but can also be malignancy (KS-IRIS).
• Little is known about pathogenesis

What is Immune Reconstitution Inflammatory Syndrome (IRIS)?

Müller et al, Lancet ID 2010.

2 Types of Immune Reconstitution Inflammatory Syndrome (IRIS)

Patient NOT on treatment for OIs Unmasking IRIS

Start ART

Patient ON treatment for OI Paradoxical IRIS

Start ART

Paradoxical: exaggerated immune response to persistent antigens of an OI that is being treated Unmasking: Exaggerated immune response to to viable pathogens that were subclinical and not being treated

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MAC Localized Disease (eg lymphadenitis, abscesses) Bacteremia absent Cryptococcus Recurrence of meningitis frequently associated w/increased ICP Lymphadenitis Cryptococcomas TB Fever, lymphadenitis, cold abscesses, worsening pulmonary disease CMV Immune recovery uveitis, can be sight threatening KS Rapid progression of KS lesion

Classic IRIS Presentations

Marais et al, Curr HIV/AIDS Reports 2009.

• PCP IRIS has been documented, but rare

Example of Paradoxical TB-IRIS

29 yo M with CD4 310, VL 380K with TB illeitis Granulomas in terminal ileum 4 weeks after ART start 6 weeks after TB treatment start FNA: AFB smear + necrotizing, granulomatous inflammation Treatment failure or TB IRIS?

• Overall incidence of IRIS is ~15-30%
• é risk if starting ARVs at a low CD4 (<50) or high VL (>100K)
• ~5% mortality in IRIS:
• 3% with TB-IRIS
• 20% with Cryptococcal Meningitis (CCM)-IRIS, risk highest if CSF WBC<5
• Risk of IRIS may be increased with dolutegravir/INSTI1

IRIS Incidence and Outcome

Müller et al, Lancet ID 2010. Novak et al, AIDS 2012.

1.Wijting I et al. CROI 2017. #731., Dutertre M et al. CROI 2017. #732.

• Step 1: Optimize or initiate treatment of the OI
• Step 2: Supportive and symptom-directed therapy (most cases are self-limiting).

Most cases resolve in several weeks.

• Step 3: Consider anti-inflammatory therapies
• NSAIDs for less severe symptoms
• Corticosteroids most commonly used for moderate to severe disease. Often start prednisone

1mg/kg and taper based on clinical response (dose for TB IRIS).

• Steroids decrease hospitalization and morbidity in TB IRIS*
• Make sure there is no evidence of Kaposis Sarcoma, steroids are contraindicated in

this case

• Don’t Stop ART!

IRIS: Treatment

Marais et al, Curr HIV/AIDS Reports 2009.

* Meintjes Lancet ID 2008

12/8/17 17

• The patient was started on NSAIDS and symptoms resolved. We

avoided steroids because patient had known Kaposi’s Sarcoma.

• Likely paradoxical IRIS
• AFB blood cultures negative
• Two months later, imaging showed improvement in abdominal LAD,

and pulmonary lesions.

Case #4: Follow-Up Key References

• DHHS 2017 OI Guidelines:

https://aidsinfo.nih.gov/contentfiles/lvguidelines/Adult_OI.pdf

• HIV Insite and Ward 86 Management Recommendations:

http://hivinsite.ucsf.edu

• AIDS Education and Training Centers’ National Resource Center:

www.aidsetc.org