Objectives Diagnose and manage common opportunistic infections (OIs) - - PDF document

1 | [footer text here]

Opportunistic Infections and Immune Reconstitution Inflammatory Syndrome

Disclosures

I have received grant funding from the National Institutes of Health and the Gilead Research Scholars Program in HIV.

Objectives

• Diagnose and manage common opportunistic infections (OIs) in HIV
• Know the indications and preferred regimens for primary

prophylaxis for OIs

• Understand the features and management of immune

reconstitution inflammatory syndrome (IRIS)

• Understand the data regarding when to start ART in the setting of

an acute OI

OIs and IRIS at MMA 2018: Dec 6 Pulmonary disease (PCP, KS, TB)

• Dr. Laurence Huang

Dec 7 Zoster and zoster vaccine

• Dr. Lisa Winston

Dec 8 Tuberculosis

• Dr. Sarah Puryear

CD4 count correlates with risk of specific OIs in untreated HIV disease

100 200 300 400 500 600 >500 200‐500 100‐200 50‐100 <50 Pneumocystis PNA Histoplasmosis PML MAC CMV Primary CNS lymphoma Pneumococcal/bacterial PNA Lymphoma Kaposi sarcoma Toxoplasmosis Cryptococcosis Cryptosporidiosis Candidal esophagitis

CD4 cell count Adapted from Bartlett JG et al. Medical Management of HIV, 2012

TB VZV/Zoster

CD4 count strata

2 | [footer text here]

Buchacz K et al. JID 2016.

With potent ART, incidence of OIs continues to decline

PCP

Candidal esophagitis MAC

N = 63,541 U.S. patients in NA‐ACCORD, 2000‐2010

• 1. CDC HIV Surveillance Supplemental Report 2018; 23(4). 2. WHO Cryptococcal Guidelines 2018.

We still see OIs in the U.S. among:

1) Patients newly diagnosed with HIV who present with an OI (late HIV dx) 2) Patients who are aware of their HIV status but face barriers to taking ART 3) Patients for whom ART fails to achieve adequate immunologic/virologic response

9% 17% 27% 33% 36% 0% 10% 20% 30% 40% 13‐24 25‐34 35‐44 45‐54 55+

Age, years

CD4 <200 or OI at HIV diagnosis United States, 20161 Globally Tuberculosis

• #1 cause of AIDS deaths

Cryptococcal meningitis2

• 223,000 cases in 2014
• 181,000 deaths
• 15% of AIDS deaths

Resources for OI management

Ward 86 Management Recommendations http://hivinsite.ucsf.edu/InSite?page=md‐ward86‐index https://aidsinfo.nih.gov/guidelines 44 y/o M with HIV

• CD4 94 cells/mm3
• not on ART or prophylaxis
• 1 month of progressive dyspnea,

non‐productive cough, fevers, night sweats, and weight loss Exam: Afebrile, 90% RA

• Diffuse crackles bilaterally and

mild wheezing Labs: WBC 8.3

• LDH 386, Beta‐D‐glucan>500
• ABG: 7.44/35/59 on room air

Case 1

3 | [footer text here]

CT Chest

A. Ceftriaxone + doxycycline B. TMP‐SMX + prednisone C. Ceftriaxone + doxycycline + TMP‐SMX + prednisone

• D. RIPE

E. Ganciclovir

Which empiric therapy would you start?

• Started on empiric CTX/doxycycline + TMP‐SMX/prednisone
• Could not obtain induced sputum
• Bronchoscopy with BAL performed for microbiologic

confirmation:

• Bacterial culture: oral flora
• AFB smear and culture: negative
• PCP positive
• TMP‐SMX + prednisone continued

Case 1 continued

• PCP = Pneumocystis pneumonia
• Caused by P. jirovecii
• ubiquitous fungus
• P. carinii now refers to the organism that infects rodents
• 90% of cases occur at CD4 <200 cells/mm3
• Most cases with CD4 <100
• Subacute presentation of nonproductive cough, progressive

dyspnea, fever

• Hypoxemia; normal lung exam or dry crackles

DHHS OI Guidelines 2018.

Pneumocystis pneumonia

4 | [footer text here]

• CXR pattern:
• Classic: bilateral, reticular interstitial infiltrates
• Pleural effusions, cavitation, intrathoracic adenopathy are rare
• May be normal
• If normal CXR  high‐resolution CT for ground glass
• High negative predictive value
• Cystic disease – increased risk of spontaneous pneumothorax
• PTX should prompt high suspicion for PCP

DHHS OI Guidelines 2018.

PCP: Imaging

See Dec 6 talk by

• Dr. Laurence Huang
• Elevated LDH: Common, non‐specific
• Plasma β‐D‐glucan
• Sensitivity 92%, specificity 65%1
• (1‐3)‐β‐D‐glucan is a component of the cell wall of most fungi
• Other causes of positive BDG: candidiasis, histoplasmosis, cryptococcus
• Dx requires microbiologic confirmation
• No culture system for P. jirovecii
• Sensitivity of stained respiratory specimen depends on method, experience of lab
• Induced (not expectorated) sputum: <50‐90%
• BAL: 95‐100%
• Organisms detectable for days‐weeks after rx
• Do not delay empiric therapy
• 1. Sax P et al. CID 2011.

PCP: Laboratory diagnostics

PCP cysts in silver‐stained bronch specimen. CDC PHIL. Disease severity Preference Regimen (21 days then start secondary ppx)

Potential toxicities Adverse effects are common

Moderate to severe PaO2 <70 A‐a grad 35 Preferred TMP + SMX (weight‐based) Adjust dose for renal function IV  PO after clinical improvement Steroids within 72 hours Prednisone 40 mg BID x 5 days Prednisone 40 mg daily x 5 days Prednisone 20 mg daily x 11 days

 Rash, fever, leukopenia, thrombocytopenia, azotemia, hepatitis, hyperkalemia

• Try to “treat through” reactions if

possible

• Desensitization protocols available

for patients with allergy

• STOP and do not re‐challenge if pt

has Stevens‐Johnson syndrome or toxic epidermal necrolysis

Mild PaO2 70 A‐a grad <35 Preferred TMP + SMX (weight‐based)

PCP: Treatment

DHHS OI Guidelines 2018. NIH‐UC Expert Panel for Corticosteroids as Adjunctive Therapy for PCP. NEJM 1990.

• If patient not improving after 3 days, is this treatment failure?
• Generally no; early worsening at 3‐5 days is common
• Wait at least 4‐8 days for a clinical response before switching therapy for

clinical failure

• Evaluate for concurrent infections as a cause for clinical failure
• consider repeat bronch

PCP: Treatment failure

DHHS OI Guidelines 2018.

5 | [footer text here]

Disease severity Preference Regimen (21 days then start secondary ppx) Potential toxicities Adverse effects are common Moderate to severe PaO2 <70 A‐a grad 35 Preferred TMP + SMX (weight‐based) Adjust dose for renal function IV  PO after clinical improvement Steroids within 72 hours Prednisone 40 mg BID x 5 days Prednisone 40 mg daily x 5 days Prednisone 20 mg daily x 11 days  Rash, fever, leukopenia, thrombocytopenia, azotemia, hepatitis, hyperkalemia

• Try to “treat through” reactions if

possible

• Desensitization protocols available

for patients with allergy

• STOP and do not re‐challenge if pt

has Stevens‐Johnson syndrome or toxic epidermal necrolysis Alternative #1 (rx failure/ toxicity) Clindamycin + primaquine + steroids Check G6PD  Anemia, rash, fever, diarrhea Alternative #2 Pentamidine IV + steroids Historically preferred. Higher mortality in retrospective studies. We avoid.  Irreversible renal and pancreatic islet cell toxicities, arrhythmias, hypoglycemia, hypotension Mild PaO2 70 A‐a grad <35 Preferred Alternative TMP + SMX Clindamycin + primaquine. Check G6PD Dapsone + TMP. Check G6PD Atovaquone BID with food  Anemia, rash, fever, diarrhea  Rash, fever  HA, nausea, diarrhea, rash, LFTs

PCP: Treatment

DHHS OI Guidelines 2018. NIH‐UC Expert Panel for Corticosteroids as Adjunctive Therapy for PCP, NEJM 1990. Ward 86 Management Recommendations, HIV InSite.

40 yo M with HIV (CD4 420 and VL <40 on DTG + FTC/TAF 1.5 years ago), lost to follow‐up. Presents with several weeks of progressive symptoms: diffuse abdominal pain, fever, diarrhea (10x per day), and cachexia

• PMH:
• HIV diagnosed 2 years ago, CD4 380, VL 80K
• Social History:
• Immigrated to CA from Mexico 20 years ago
• Marginally housed
• Labs:
• Hgb 7, normal LFTs, Cr 1.0
• CD4 48 (6%), VL pending

Case 2

• CT shows bulky necrotic nodes in mediastinum and retroperitoneum

Case 2 continued

• Numerous pulmonary nodules in UL and RML, largest 1.8 cm

CT chest

6 | [footer text here]

A. Cytomegalovirus (CMV) B. Mycobacterium tuberculosis (TB) C. Mycobacterium avium complex (MAC)

• D. Lymphoma

What is the most likely diagnosis?

Syndromic differential can help predict pathogens in patients with CD4<50

Short DDx in AIDS: Fever + wasting + lymphadenopathy Disseminated MAC Tuberculosis Disseminated fungal (Histo, Crypto) Lymphoma Short DDx in AIDS: AIDS + prolonged diarrhea Parasites (cryptosporidium, microsporidium) Bacterial (Salmonella, Shigella), mycobacterial (MAC; TB ileitis) Viral: CMV colitis Fungal: Histoplasmosis Other: HIV enteropathy, Malignancy: lymphoma, Kaposi sarcoma (HHV8) Short DDx in AIDS: AIDS + pulmonary nodules Tuberculosis Fungal (Crypto, Coccidioidomycosis) Kaposi sarcoma Lymphoma

• Stool cultures and O&P ‐ Giardia Ag positive
• Serum Cryptococcal Ag (CrAg) ‐ negative
• Urine Histoplasma Ag ‐ negative
• Sputum AFB smear x3 ‐ negative
• AFB blood cx drawn; started on empiric treatment for MAC
• Restarted ART: Dolutegravir + FTC/TDF
• switched from FTC/TAF due to drug interaction with rifabutin

Case 2 continued When to suspect Mycobacterium avium complex

Clinical:

• Fever, weight loss, +/‐ diarrhea,

+/‐ abd pain Laboratory:

• CD4 <50
• Elevated alkaline phosphatase
• Anemia/pancytopenia due to bone

marrow infiltration Diagnostics:

• AFB blood cultures*
• Sensitivity 91% for 1 AFB BCx
• Sensitivity 98% for 2 AFB BCx
• CT abdomen often reveals HSM

and intrabd. lymphadenopathy

• May need tissue bx

Benson and Ellner. CID 1993. *draw prior to azithromycin

7 | [footer text here]

Drug 1: Macrolide Drug 2 +/‐ Drug 3 +/‐ Drug 4 Clarithromycin (more data) OR Azithromycin (better tolerated, fewer drug interactions) Ethambutol Rifabutin* Moxifloxacin Levofloxacin Ciprofloxacin Amikacin Streptomycin

Karakousis PC et al. Lancet Infect Dis 2004. DHHS OI Guidelines 2018. Ward 86 Management Recommendations, HIV InSite.

MAC Treatment: At least two drugs

• Consider a 3rd drug if high burden of disease or pt not on ART
• Monitoring:
• Repeat AFB blood cx at 4 weeks
• Consider treatment failure if
• still bacteremic after 4 weeks of rx
• no improvement in sx
• Duration: at least 1 year and CD4 >50

*check for drug interactions; e.g. do not use rifabutin with TAF or BIC

Primary MAC prophylaxis: Evolving guidelines

• DHHS guidelines:2 ppx until CD4 >100 (last updated 2013; in progress)
• IAS‐USA guidelines3 no longer recommend primary MAC ppx
• Our practice at Zuckerberg San Francisco General Hospital:4
• If patient has signs/symptoms of dMAC
• Start empiric MAC treatment + ART
• Monotherapy for MAC macrolide resistance; MAC IRIS can be severe
• If patient does not have signs/symptoms of dMAC
• Start primary ppx + ART; D/c ppx when VL <1000 regardless of CD4
• 1. Yangco BG et al. AIDS Pat Care STDs 2014. 2. DHHS OI Guidelines 2018. 3. Saag M et al. JAMA 2018.
• 4. Ward 86 Management Recommendations, HIV InSite.

369 patients with CD4 <50 on ART in HIV Outpatient Study, 1996‐20071 11 incident MAC infections 0 in patients with HIV RNA <1000 c/ml regardless of whether on ppx OI

CD4 threshold Regimen of choice and alternative regimens

When to stop primary ppx (in pts on ART)

Secondary ppx/ chronic maintenance

PCP

CD4<200

• r

CD4<14%

• TMP‐SMX 1 DS daily
• TMP‐SMX 1 SS daily
• TMP‐SMX 1 DS 3x/wk
• Dapsone1,2
• Aerosolized pentamidine2
• Atovaquone w/ meal

CD4>200 x >3 mo and VL ND OR CD4 >100 and VL ND x3‐6 mos4,5

Toxoplasma gondii

CD4<100 and Toxo IgG+

• TMP‐SMX 1 DS daily
• TMP‐SMX 1 DS 3x/wk
• Dapsone/pyrimethamine

+ leucovorin1

• Atovaquone w/ meal

CD4>200 x >3 mo and VL ND OR CD4 >100 and VL ND x3‐6 mos6

MAC

CD4<50 and no evidence

• f dMAC
• Azithro 1200 mg weekly
• Azithro 600 mg 2x/wk
• Rifabutin 300 mg daily3

CD4>100 x >3 mo and VL ND7 OR VL <1000 regardless of CD48

• 1. Check for G6PD deficiency. 2. Does NOT provide Toxoplasma ppx 3. Monitor for drug interactions, eval. for active TB. 4.

Prophylaxis of OIs: The basics Back to case: Underwent colonoscopy and lung biopsy

8 | [footer text here]

Colon biopsy: Granulomatous inflammation with AFB

Blood cx turned positive for MAC

Colon biopsy: Cytopathic changes consistent with CMV

Nucleomegaly and eosinophilic nuclear inclusion

Lung nodule biopsy: Kaposi sarcoma

Stains for HHV8+

Diagnoses: 1) Disseminated MAC 2) CMV colitis 3) KS

Occam’s razor does not apply – consider multiple concurrent OIs or conditions

H&E: spindle cells

Usually occurs when CD4<50

• Reactivation of latent infection

CMV EOD (in order of frequency):

• Retinitis:
• Diagnosed by dilated exam by

experienced ophthalmologist

• Colitis, esophagitis:
• Tissue dx: visual or endoscopic

evidence of erosion or ulcers with CMV inclusions on path

• Neuro: encephalitis, polyradiculitis,

myelopathy

• Clinical dx; CSF CMV DNA confirmatory
• Pneumonitis: very rare in AIDS, usually

bystander in BAL

AIDS‐related CMV end‐organ disease

Diagnostics

• CMV serology, serum

PCR, and viral culture not helpful

• Patients with CMV GI
• r neurologic disease

should have dilated eye exam

DHHS OI Guidelines 2018.

9 | [footer text here]

Three weeks after re‐starting ART, the patient was readmitted with new fever to 39.4, worsening abdominal pain. CT showed mild increase in size of mediastinal/intra‐abdominal lymph nodes and bowel wall enhancement. CD4 increased from 46 ‐> 85, and VL 200K ‐> 18K. Labs are otherwise unchanged.

Case 2 continued

A. Medication nonadherence B. New OI C. IRIS

• D. Treatment failure

E. All of the above

What is on your differential diagnosis?

• Immune reconstitution inflammatory syndrome (IRIS)
• Adverse med effect
• Treatment failure
• Nonadherence
• Drug resistance*
• Poor absorption of medications
• New OI
• Malignancy
• Autoimmune condition

* In dMAC, susceptibility testing for clarithromycin (but no other drugs) correlated with clinical response

DDx: Worsening clinical status after starting ART in setting of OI

• Syndrome of exaggerated immune response to antigens AFTER

ART start

• ~1 week to 3 months after ART start with decrease in VL +/‐

increase in CD4

•  risk if starting ART at low CD4 (<50) or high VL
• Usually due to infections but can be due to malignancy (e.g. KS)
• Incidence and presentation vary by OI
• ~30% of patients with dMAC
• PCP IRIS2 is uncommon
• Can be benign and self‐limiting or severe, esp. with CNS disease
• * Diagnosis of exclusion: Evaluate for alternative causes of clinical

worsening (treatment failure, drug resistance, other infection, etc.)

What is Immune Reconstitution Inflammatory Syndrome (IRIS)?

• 1. Müller M et al. Lancet Infect Dis 2010. 2. Jagannathan P et al. AIDS 2009.

10 | [footer text here]

Paradoxical versus unmasking IRIS

Patient NOT on treatment for OI Unmasking IRIS

Start ART

Patient ON treatment for OI Paradoxical IRIS

Start ART

Can be severe, e.g. in cryptococcal meningitis More common in U.S. Step 1: Continue ART (except if patient has encephalitis) Step 2: Optimize or initiate treatment of the OI

• Evaluate for alternative causes of clinical worsening

Step 3: Supportive and symptom‐directed therapy

• Most cases resolve in several weeks of continuing ART and OI rx

Step 4: Consider anti‐inflammatory therapies

• Consider NSAIDs for less severe symptoms (limited data)
• Corticosteroids for moderate to severe disease
• Often start prednisone 1mg/kg and taper based on clinical response
• Best evidence for TB;1 we also use in MAC
• Consider in CMV immune‐recovery uveitis, severe CM IRIS
• Try to minimize course – infectious complications w/ prolonged steroids
• Make sure no evidence of Kaposi sarcoma  steroids can cause rapid,

fatal worsening

IRIS: Management

Marais et al. Curr HIV/AIDS Rep 2009. Ward 86 Management Recommendations, HIV InSite.

• 1. Meintjes G et al. AIDS 2010.

YES in TB!1

• CD4 ≤100 & TB
• Prednisone vs placebo at ART

start

• Lower incidence TB‐IRIS in

prednisone arm (33%) vs placebo (47%) No in cryptococcal meningitis2 Dexamethasone arm vs placebo:

• Higher mortality and disability
• Slower clearance of fungal cx

Steroids for prevention of IRIS

• 1. Meintjes G et al. NEJM 2018. 2. Beardsley J et al. NEJM 2016.
• The patient was started on NSAIDs. Symptoms improved over time.
• Steroids avoided due to KS
• Repeat AFB blood cultures negative (unlikely treatment failure)
• Likely paradoxical IRIS
• Two months later, imaging showed improvement in abdominal LAD

Case 2: Follow‐Up

11 | [footer text here]

Case 3

51 M with PMH of diverticulitis presents with

• 1 month of progressive dyspnea on

exertion, dry cough

• Sweats, fevers, 10 lb weight loss
• Noticed a pimple on forehead that

had ruptured and left open wound Exam:

• Afebrile, lungs clear, A&O, fluent

speech

Studies at presentation

• Rapid HIV Ag/Ab (+)

Waiting for CD4 result? Normal absolute lymphocyte count has 96% predictive value for CD4 >100 cells/mm3

Jacobson MA et al. AIDS 2003.

\ 13.0 / 5.4 ‐‐‐‐‐‐ 209 / 39.8 \

N 78%, L 16.6%, M 23%

Studies at presentation

• Rapid HIV Ag/Ab (+)
• Serum CrAg (+) 1:32,768

Waiting for CD4 result? Normal absolute lymphocyte count has 96% predictive value for CD4 >100 cells/mm3

Jacobson MA et al. AIDS 2003.

\ 13.0 / 5.4 ‐‐‐‐‐‐ 209 / 39.8 \

N 78%, L 16.6%, M 23% A.

Perform LP to evaluate for meningitis

B.

Initiate fluconazole for cryptococcal pneumonia

What is your next management step?

12 | [footer text here]

• Order serum CrAg if CD4 <100 and any of the following:
• fever, headache, AMS, pneumonia1
• consider if asymptomatic and starting ART (expert opinion)2
• Perform LP if newly positive serum CrAg
• even if asymptomatic

Cryptococcal meningitis can present without headache or AMS

DHHS OI Guidelines 2018. 1. Ward 86 Management Recommendations. HIV InSite. 2. Data stronger for higher prevalence settings in LMIC countries. Primary ppx in absence of positive CrAg not recommended in U.S.

Case 3 continued

• CD4 = 39
• 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
• Skin bx cx
• C neoformans
• Blood cx
• C neoformans
• Major cause of AIDS deaths globally
• Most cases occur when CD4<100
• Clinical:
• Presents as subacute meningitis or meningoencephalitis
• Can see encephalopathic signs/sx due to elevated ICP
• Diagnosis:
• Serum and CSF CrAg are almost always positive
• CrAg used for diagnosis, NOT evaluating response to therapy –

need CSF culture

• CSF studies: lymphocytic pleocytosis, mildly elevated protein
• Low CSF WBC (or no WBC) portends a poorer prognosis
• CSF culture is gold standard

DHHS OI Guidelines 2018

Cryptococcal meningitis

Manifestations of cryptococcosis

(often disseminated):

• Meningitis
• Pulmonary disease
• Lymphadenopathy
• Umbilicated skin lesions

Cryptococcal meningitis: Treatment

Phase and duration Regimen Potential toxicities

Induction At least 14 days Liposomal amphotericin B* AND Flucytosine (5‐FC)

Amphotericin:

• Creatinine elevation, electrolyte

abnormalities (hypoK, hypoCa), anemia, infusion reactions

• Daily monitoring of Cr and lytes
• Give with IV fluids (normal saline)

Flucytosine:

• GI disturbance, cytopenias
• Dose‐adjust in renal impairment

If patient improving + repeat CSF culture negative Consolidation 8 weeks Fluconazole 400mg (6mg/kg) daily

• Rash, LFT elevations
• Potential for drug interactions

Chronic maintenance At least 1 year AND CD4>100 and VL ND x3 months on ART Fluconazole 200mg daily

DHHS OI Guidelines 2018. * Liposomal formulation preferred if available

13 | [footer text here] Elevated ICP

• can cause clinical deterioration even with microbiologic response
• leading cause of death from CM in the first 2 wks after diagnosis

Management:

• Measure OP at diagnosis
• If OP is elevated >20 cm H2O and pt has sx:
• LP every 12‐24 hours
• Remove volume (~20‐30cc) to lower OP to 20 cm H2O or by 50%
• Aim for at least 2 days of stable pressures
• Consider lumbar drain if sx persist (refractory headache, N/V,

confusion, clonus, papilledema) despite daily LPs

• Ventriculoperitoneal shunt should only be placed in exceedingly

rare circumstances (cannot control ICP after 2‐4 wks of maximal rx)

DHHS OI Guidelines 2018. Ward 86 Management Recommendations, HIV Insite.

CM: Mainstay of management is control of elevated intracranial pressure When should you start ART?

A. Now B. After 2 weeks C. After 6 weeks

• D. After 10 weeks

Advantages

• Slow HIV progression
• Sometimes ART is the best

treatment for the OI

• PML, cryptosporidiosis,

microsporidiosis

• Prevention of a second OI
• Restore pathogen‐specific

immunity

• more rapid clearance of OI

Disadvantages

• Risk of IRIS
• especially in CNS or eye

Starting ART during an acute OI

• 282 patients with acute OI or serious bacterial infection
• 63% PCP, 12% cryptococcus, excluded TB; median CD4 29
• Randomized to ART start:
• “Early” = within 2 wks of starting OI rx (median 12 days)
• “Deferred” = after OI rx complete (at 6‐12 wks) (median 45 days)
• Lower risk of AIDS progression/death in early arm
• 14% in early vs 24% in deferred arm; p = 0.035
• Few IRIS cases (6% in early vs 9% in deferred arm)

Zolopa A et al. PLoS ONE 2009

14 | [footer text here]

When to start ART in cryptococcal meningitis?

COAT Trial: 177 pts in Uganda + S. Africa CM Rx:

• Amphotericin B +

Fluconazole 800 mg x 2wks

• Fluc 800 until CSF sterile
• Fluc 400 x 8wks

Boulware D et al. NEJM 2014.

Considerations for generalizability:

• Used fluconazole instead of flucytosine
• Repeat LPs may have been less available

DHHS guidelines: wait 2‐10 weeks Earlier ART (n=88) Deferred ART (n=89) Days to ART start, median (IQR) 9 (8‐9) 36 (34‐38) Death by 6 months CSF WBC <5 cells/mm3 45% HR 2.21 (0.91‐5.34) 30% ref p=0.03 p=0.008 CCM‐IRIS 16.2% 10.1% p=0.347 Stopped early ‐ excess mortality

Deferred ART Earlier ART

• Prob. of survival

The Zuckerberg San Francisco General Hospital Experience After starting OI therapy we wait 14 days prior to starting ART:

• Cryptococcal meningitis
• We wait at least 14 days
• Inflammatory CNS lesion
• Brain edema, mass effect, or neurologic deficit. Limited data.
• CMV retinitis
• Limited data1
• TB meningitis

When NOT to immediately start ART in the setting of an acute OI?

Ward 86 Management Recommendations, HIV InSite. 1. Orgeta‐Larrocea G et al. AIDS 2015.

37 y/o M with HIV

• CD4 28
• ff ART and prophylaxis
• presents with fever, altered

mental status, and seizure

Case 4 What is on your differential diagnosis?

A. Primary CNS lymphoma B. Toxoplasmosis C. Pyogenic brain abscess

• D. All of the above

15 | [footer text here] Long Differential

Skiest DJ. CID 2002. Chamie G et al. Semin Neurol. 2014

Selected differential diagnosis of focal neurologic disease in AIDS

Short Differential

• Toxoplasma gondii
• Primary CNS

lymphoma

Bacterial

• Pyogenic abscess
• Nocardia
• Tuberculoma/NTM
• Syphilis

Fungal

• Cryptococcoma
• Histoplasma
• Aspergillus

Viral

• Progressive

multifocal leukoencephalopathy (JC Virus)* Malignancy

• Primary CNS

lymphoma

• Metastases

Parasitic

• Toxoplasma gondii
• Trypanosoma cruzii

(chagoma)

* PML: White matter

• nly, no mass effect,

non‐enhancing except in PML‐IRIS

• Occurs at CD4<100
• Disease almost exclusively due to reactivation of latent infection
• Transmission occurs by ingesting oocysts excreted in cat feces (litter/soil),

undercooked meat (pork and lamb) or raw shellfish containing tissue cysts

• Seroprevalence in the US is 3‐30%; higher globally
• Subacute presentation over several weeks:
• HA, fever, behavioral changes, confusion, hemiparesis, seizures, ataxia, CN

palsies

• Toxoplasma can rarely cause disseminated disease
• Pneumonitis (can mimic PCP), retinitis

DHHS OI Guidelines 2018. Skiest DJ. CID 2002.

Toxoplasmic encephalitis: Epi and clinical

• Lesions can be single or multiple:
• Classic: ≥2 ring‐enhancing lesions with surrounding edema
• 27%–43% of patients have a single lesion
• Rare: diffuse encephalitis with no focal lesions
• Serum Toxoplasma IgG:
• If negative, virtually excludes infection
• <3%–6% of patients with TE have negative IgG
• CSF studies:
• Normal or mild increase in protein, lymphocytic pleocytosis,

low glucose

• Toxo CSF PCR: Sens ~50%, spec 96‐100%. Does not r/o disease.
• EBV DNA, cytology (CNS lymphoma), other studies as

appropriate

Toxoplasmic encephalitis: Imaging and diagnosis

Skiest DJ. CID 2002.

In practice: a clinical diagnosis based on low CD4, Toxo IgG+, imaging 1) Treat empirically 2) Repeat MRI in 2 weeks 3) If no improvement in exam/imaging, consider other diagnoses and brain biopsy Preference Regimen Potential toxicities First‐line pyrimethamine (weight‐based) + sulfadiazine (weight‐based) + leucovorin Duration: at least 6 weeks

• then chronic maintenance therapy:

pyrimethamine + sulfadiazine + leucovorin (also provides PCP ppx) Pyrimethamine: rash, nausea, and bone marrow suppression (can treat by increasing leucovorin dose) Sulfadiazine: rash, fever, leukopenia, hepatitis, nausea, vomiting, diarrhea, and crystalluria  acute kidney injury (encourage hydration)

Alternative (clinical failure/ toxicity)

• pyrimethamine + leucovorin +

clindamycin*

• TMP/SMX alone**
• atovaquone + pyrimethamine +

leucovorin

• atovaquone + sulfadiazine
• atovaquone

Toxoplasmic encephalitis: Treatment

For dosing, refer to DHHS OI Guidelines 2018.

* Preferred. Does not provide PCP prophylaxis.

** If pyrimethamine unavailable/delay in obtaining, should use TMP/SMX. Avoid steroids (if possible) if treating empirically – will also treat lymphoma

16 | [footer text here]

• The patient was Toxo IgG+ and started on empiric therapy for

Toxoplasmosis

• CSF EBV DNA and cytology negative
• He improved over the next 2 weeks and a biopsy was deferred

Back to the case… Key points

• OI incidence declining; still important cause of morbidity/mortality
• CD4 count guides differential diagnosis in pts with untreated HIV
• Occam’s razor does not apply – consider multiple concurrent OIs
• OIs can be prevented with ART and primary and secondary ppx
• Indication for ppx depends on CD4 cell count and viral suppression
• New data on primary ppx for MAC
• Start ART as soon as possible – except in specific situations:
• Cryptococcal meningitis; TB meningitis; ocular OIs – CMV retinitis
• CNS lesion with edema/mass effect, neurologic deficit
• Increased risk of IRIS with low CD4
• Evaluate for other etiologies of worsening, continue ART
• Steroids may be beneficial for treatment; minimize duration, avoid in KS
• Data support steroids for prevention of IRIS in TB, not CM

Acknowledgements

Diane Havlir Meg Newman Annie Luetkemeyer Monica Gandhi Mark Jacobson Carina Marquez Gabriel Chamie Jen Babik Vivek Jain Laurence Huang