Jill Blumenthal, MD of the UC San Diego AntiViral Research Center presents "Cryptococcal Meningitis with Cranial Nerve Neuropathies: Predictors of Outcome and Review of ART Initiation"

1. AIDS CLINICAL ROUNDS
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2. Cryptococcal Meningitis with Cranial
Nerve Neuropathies: Predictors of
Outcome and Review of ART Initiation
AIDS Rounds
11/16/12
Jill Blumenthal, ID Research Fellow

3. History of Present Illness
• RG is a 39M with HIV (CD4 14/4%, VL 40,519 VL) not
on ART presents with worsening HA, neck stiffness,
diplopia, n/v x1 week
• Noticed diplopia 1 week ago while driving, worse when
looks left
• HAs intermittent, pulsaltile worse with movement.
• + photophobia and phonophobia; lightheaded
• Intermittent “sparkles” in vision
• No fevers (but subjective warth), chills or sweats
• ROS: +20lb weight loss over 7 months. Thrush and
dysphagia. Rash on soles of feet x2 months. No CP,
SOB or diarrhea

4. History
PMH: FHx: HTN in mom, Diabetes
• Prior treatment for in dad
Tuberculosis as a child
• Diagnosed with HIV in SHx
2/2012 at North Park • MSM
• No IVDU. Used to snort
Meds: None meth/coke. No EtOH
• 5 pack-year smoking
All: None history, quit 6 months ago

5. Physical Exam
• VS: T 99.5 BP 145/90 HR 107 RR 18 O2 99% RA
• General: NAD, AOx3
• OP with thrush and pustular lesions on OP
• Neck: LAD on anterior chain, supple, no meningeal
signs
• CV: RRR, no m/r/g
• Lungs: CTAB
• Abd: soft, NT, ND +BS
• Back: No spinal or paraspinal tenderness
• Extremities: no edema
• Skin: violaceous macular non-painful, non-pruritic
lesions on medial aspect of right foot and along lateral
malleolus of L foot

6. Ophthalmologic Exam
• Visual Acuity: 20/20
• EOMI Full on OD, OS no full abduction
• Sclera: Without lesions
• Fundoscopic exam: Mild blurring of disc
margins but flat macula
• Cotton wool spots in superior left eye
• No vitritis or retinitis

7. Neurologic Exam
• CN: II-XII intact with the exception of bilateral 6th
nerve palsies, left slightly worse than right.
• Motor: Normal bulk, power and tone in all four
extremities. No tremors or drift.
• Sensory: Normal light touch, proprioception, pin
sensation, and temperature sensation in all four
extremities.
• DTRs: 2/4 all 4 extremities, downgoing toes b/l
• Coordination: Normal. Gait stable with narrow base.

8. Labs
126 88 11
120
3.6 29 0.71
Albumin 3.2
11.7 AST 23
5.8 194 ALT 38
Alk Phos 67
T Bili 0.3
96% PMNs, 3% Lymphocytes

9. Imaging
• 7/22 CT head non-con: No evidence of
intracranial hemorrhage, mass effect or midline
shift. White matter hypoattenuation involving the
bilateral corona radiata may represent ischemic
changes, demyelination versus gliosis.
However, small parenchymal mass lesions
cannot be excluded.

10. CSF
• Opening Pressure in ED recorded as
18cm H20
• Tube 4: WBC 19 (82L, 3N, 14M) RBC 2
Glc 2 Prt 20
• Culture, India Ink, VDRL, CrAg, Cocci
serologies, AFB, HSV sent

11. 2 small foci of restricted diffusion, one within right corona radiata and the other within the left
globus pallidus. Numerous punctate foci of T2 prolongation within periventricular and subcortical
white matter and confluent areas of T2 prolongation in posterior perventricular WM. Dilated
perivascular spaces and diffuse T2 prolongation within the basal ganglia b/l c/w gelatinous
pseudocysts. Increased signal on FLAIR within subarachnoid space b/l with mildly increased
leptomeningeal enhancement

12. CSF
CSF CrAg Culture
7/22 1:1024 C. Neoformans
7/24 1:65,536 C. Neoformans
7/26 1:131,072 C. Neoformans
7/27 1:131,072 C. Neoformans
7/31 Negative

13. Microbiology
• Bcxs at admission 7/21 grew C.
neoformans 2/4, cleared 7/22
• 7/22 Serum CMV PCR 1854
• 7/22 mouth lesion: Herpes simplex +
• 7/23 Hepatitis B cAb Positive
• 7/23 Hepatitis B sAb 538
• 7/25 Serum CrAg 1:262,144

14. Regimen
Cryptococcal Meningitis: Ampho B 300mg daily
and flucytosine 1500mg q8h x2 weeks
fluconazole 400mg daily
HSV Esophagitis: Acyclovir 800mg TID
CMV viremia/CNS disease: Ganciclovir induction
5mg/kg IV q12 x2 weeks valgancyclovir
900mg daily
Prophylaxis: Azithromycim, Bactrim

15. What are the predictors of
poor clinical outcome of CM in
HIV-infected patients?
•Do high CrAg titers predict
elevated ICP?

16. •Aims: Prevalence and predictors of AIDS-related complicated
CM
•1990-2009, 82 patients with first episode CM identified, 14
(17%) met predefined criteria
•Findings: focal neuro exam, abnormal head CT and large
crypto burden measured by CrAg titer in CSF were a/w
outcome of complicated CM
•Opening pressure >30 cm not significant when controlling
for focal neuro deficit, CT abnormality and CSF Ag titer
•CrAg (serum and CSF) moderately correlated with initial CSF
opening pressure
AIDS Research and Therapy 2010, 7:29

17. •Aims: Impact of serial LPs on association between CSF opening pressure and
prognosis, time course and relationship of opening pressure with neuro
findings, CSF fungal burden, immune response and CD4 count
•163 HIV-positive ART-naive patients in trials of ampho B-based tx
fluconazole in Thailand and South Africa
•Patients with higher baseline fungal burden (as measured by CSF CFU) had
higher baseline opening pressure
•High fungal burden NECESSARY but not sufficient for developing high
pressure
•Baseline opening pressure not a/w CD4 count, CSF CrAG, CSF cytokines or
AMS
AIDS 2009, Vol 23 No 6.

18. •Aims: Baseline prognostic factors for clinical outcomes
•Prospective, randomized controlled trial
•140 subjects in Thailand and USA ampho B x 2 weeks followed
by 56d of fluconazole 400 vs 70d fluconazole 400 vs 70d
fluconazole 800
•At D14, characteristics a/w poor composite outcome: low
baseline weight, high baseline CSF CrAg titer and low baseline
CSF WBC
•At D70, characteristics a/w poor composite outcome: baseline
CSF CrAG >1:1024 and low baseline Karnofsky
•Patients with + CSF culture at D14 of tx had worse survival
Intern Jour STD & AIDS Vol 22 Nov 2011

19. What about HAART?
•Incidence of IRIS?
•Mortality associated with ARV
initiation during CM treatment?
•When to start?

20. When would you start HAART in
this patient?
1. Immediately
2. After completion of CM induction therapy
3. In 1 month
4. In 3 months
5. At follow up when patient is clinically
stable

21. • Aim: Incidence, characteristics, risk factors for CM-IRIS
• Cape Town, South Africa
• February 2005–July 2006
• 118 patients and followed for 1 year
• 18 were on ARVs at start, 35 died before ART, 65 started
47 days (38-65) from CM diagnosis (prospective)
• HAART: (stavudine, lamivudine and nevirapine or
efaviernz) 4 weeks from CM diagnosis
J Acquir Immune Defic Syndr. 2009. 51: 130-134.

22. 11 of 65 patients with IRIS at 4
weeks from starting
J Acquir Immune Defic Syndr. 2009. 51: 130-134.

23. No significant difference in death in
IRIS group
J Acquir Immune Defic Syndr. 2009. 51: 130-134.

24. Conclusions
• Patients developing IRIS had more rapid immune
restoration in response to ART
• Trend in those who developed IRIS to have a higher
fungal burden at end of induction therapy
• No difference in mortality
• No difference in cytokine profiles in CSF
• Deferring ART based on risk of mortality from IRIS must
be weighed against risk of mortality from advanced HIV,
esp in low-income countries
• Based on this cohort, authors conclude that ART should
be started between 2 - 4 weeks from start of antifungals
J Acquir Immune Defic Syndr. 2009. 51: 130-134.

25. Limitations
• Data from 2 different studies (CID 2007.
45: 76-80. and CID 2008. 47: 123-130)
but there was no difference in rate of IRIS
(3/18 and 8/47)

26. • Aim: Incidence, Relationship between timing of HAART and
IRIS, Risk Factors for IRIS
• Prospective, Phase II, Multicenter, Randomized Clinical Trial
• Patients followed for 6 months
• Standard therapy: Amphotericin for 14 days + fluconazole 8
weeks (either 400 or 800mg)
• Encouraged to delay HAART for up to 6 weeks
CID. 2009. 49:931-934

27. No association between timing of
HAART initiation and IRIS
•Median Interval from HAART initiation to IRIS was 63 days
•3/13 (23%) IRIS patients versus 16/88 (18%) non-IRIS
patients started HAART on or before day 42 (p=.71)
CID. 2009. 49:931-934.

28. CSF characteristics of the 13/101
patients developed IRIS
CID. 2009. 49:931-934

29. Conclusion: Clinical outcome better
with HAART
• Risk Factor: Baseline serum CrAg titer was
associated with increased risk of IRIS (1:512 vs
1:128)
• No difference in mortality between IRIS and non-
IRIS, though more adverse effects in IRIS
patients (papilledema and decreased levels
consciousness)
• Probabilities of successful outcomes at days 14,
42, and 70 and survival to 6 months was higher
for HAART.
• Limitations: Followed for only 6 months
CID. 2009. 49:931-934.

30. • Review of studies from 1996 to 2009
• Aim: To define mortality in patients with IRIS in different
income countries
• 54 cohort studies from 22 countries
• High Income: Australia, France, Ireland, Japan, South
Korea, Spain, UK, Germany, Taiwan, US
• High-Middle Income: Argentina, Brazil, Mexico, Poland,
Serbia, South Africa, Venezuela
• Low-Middle: India and Thailand
• Low Income: Cambodia, Mozambique, Senegal
Lancet Infectious Disease 2010. 10: 251-261.

31. Rates of IRIS with Cryptocococcal
meningitis
• 21% of IRIS with patients diagnosed with cryptococcal meningitis
• IRIS 28% of patients with CD4<50
• IRIS 2% of patients with CD4>50
• IRIS greater in higher income than lower income countries
Lancet Infectious Disease 2010. 10: 251-261.

32. • Open-label, randomized, phase IV with 283 subjects who
presented with AIDS-related OIs or serious bacterial infections
• May 2003 to August 2006, recruitment at 39 ACT Units in US
and South America
• Early Arm – Start ART within 48 hours of study enrollment,
within 14 days (n=142)
• Deferred Arm – Start ART between week 6 and 12 (n=141)
• Followed for 48 weeks
• HAART: PI/r + 2 NRTIs vs NNRTI+ 2NRTIs (3TC or FTC)
PLoS One. 2009. 4: e5575

33. Findings
• Most common OIs (not including TB)
– PCP 63%
– Cryptococcal Meningitis 12%
– Bacterial Infections 12%
• 20 cases of IRIS in this study (7%)
• 35 cases of cryptococcal meningitis (13 in
early arm and 22 in deferred arm)
• The difference in the primary endpoint did
not reach statistical significance
PLoS One. 2009. 4: e5575

34. Early ART favored
in patients with:
CD4<50
Fungal OIs
(including
cryptococcus
and
histoplasmosis)
PLoS One. 2009. 4: e5575

35. Lower Likelihood of AIDS progression
or death in Early Arm
PLoS One. 2009. 4: e5575

36. •Prospective, open-label randomized trial in Zimbabwe
•1st CM dx, randomized to early ART (within 72h after CM dx) or delayed
ART (after 10 weeks of tx with fluconazole alone)
•All subjects were inpatients taking fluconazole 800mg daily
•ART: d4T, 3TC and nevirapine twice daily
•Duration of follow up 3 years, primary endpoint all-cause mortality
•54 enrolled (28 in early, 26 in delayed)
•3 year mortality differed significantly between early and delayed ART (88 vs
54%, p<.006)
•Study terminated early by DSMB
CID 2010, Vol 50 (June 1)

37. Early treatment a/w increased mortality
Risk of
mortality
almost 3X as
great in early
ART group vs
delayed (AHR
2.85, CI 1.1-
7.23)
CID 2010, Vol 50 (June 1)

38. Conclusions/Limitations
• In resource-limited settings where CM management may
be suboptimal, early initiation of ART results in increased
mortality
• Possible reasons: suboptimal management of CM via
monotherapy with fluconazole, inadequate CSF pressure
management, drug-drug interactions and IRIS
• Early initiation ?alteration of CNS and peripheral
cytokine profiles, limiting CNS clearance
– Early ART results in pro-inflammatory state IRIS
• Limitations: small sample size, lack of blinding, overall
CM management suboptimal, no drug resistance testing
• Recommendation: Wait at least 10 weeks for ART after
starting CM tx in resource-limited settings
CID 2010, Vol 50 (June 1)

39. • Aims: Incidence, Clinical presentation, Outcomes and
Cytokine profiles of CM-IRIS
• Kampala, Uganda May 2006 to September 2009
• 101 ART naïve patients
• CM: Amphotericin B x 2 weeks  400mg fluconazole daily
• ART: Started median 34 days (24-41 days)
• ART: AZT, 3TC, efavirenz OR d4T, 3TC and nevirapine
PLoS Medicine 2010. 7: e1000384

40. Risk Factors for IRIS
• Pre-ART
serum CrAg
associated
with increased
likelihood of
IRIS
PLoS Medicine 2010.
7: e1000384

41. Increased Mortality with IRIS
•Overall Mortality 28/101 (27%)
•45 patients with IRIS
•16/45 (36%) with IRIS died
•12/56 (21%) without IRIS died
•NO difference in incidence of
IRIS in those starting ART 11-28d
and those who waited >28d (44
55%, p=0.4)
PLoS Medicine 2010. 7: e1000384

42. Are there other markers to
predict IRIS?
•Are there biomarkers a/w
development of IRIS?
•Can we reliably use them to
predict occurrence?

43. • Mathematical Model to predict IRIS and
Mortality using other serum biomarkers
• Future CM-IRIS associated with elevated pre-
ART CRP, IL-4,and IL-17.
• Increased IL-4 ineffective antigen
clearance predisposition to develop IRIS
• IL-17 in the Th17 pathway previously
hypothesized as important in IRIS
pathogenesis
• Lower levels of TNF-alpha (part of innate
immune response, pro-inflammatory), VEGF
and GCSF had an increased risk of IRIS
PLoS Medicine 2010. 7: e1000384

44. Can we predict IRIS risk?
Mathematical model based on pre-ART serum levels of IL-4, IL-
17, G-CSF, GM-CSF, CCL2 (MCP-1), TNF-alpha, and VEGF
PLoS Medicine 2010. 7: e1000384

45. CRP> 32 mg/L alone associated
with decreased survival
PLoS Medicine 2010. 7: e1000384

46. Elevated IL-17, CRP>32 and low GM-
CSF associated with increased
mortality
PLoS Medicine 2010. 7: e1000384

47. Conclusions/Limitations
• Pre-ART increases in Th17 and Th2 responses
(e.g., IL-17, IL-4) and lack of proinflammatory
cytokine responses (e.g., TNF-α, G-CSF, GM-
CSF, VEGF) predispose individuals to
subsequent IRIS
• Biomarkers could be an objective tool to stratify
risk of CM-IRIS and death and guide when to
start ART
• No causality, heterogeniety of inflammatory
profiles, validation required
PLoS Medicine 2010. 7: e1000384

48. •Prospective cohort of 199 HIV-infected, ART-naïve Ugandans with first
CM episode, 170 had clinical data copllected
•July 2006-2009
•Ampho for 14 days fluconazole 400mg daily
•Of 170 patients, 85 survived to initiate ART at median 5 weeks
•33 (39%) developed paradoxical CM-related IRIS with CNS
manifestations at median 8 weeks
•Another 9 with likely crypto-related IRIS with non-CNS manifestations
•At CM dx, subjects who went on to develop IRIS had less inflammation
with decreased CSF leukocytes, protein, INF-γ, IL-6, IL-8 and TNF-α
•CM relapse a/w persistent lack of viable organisms or inflammation in
CSF
JID 2010 vol 202 Sept 15

49. Can we use CSF cytokine profiles to
clinically risk stratify HIV-infected
patients starting ART?
JID 2010 vol 202 Sept 15

50. General Conclusions
• Baseline high serum CrAg and fungal burden
associated with increased risk of IRIS.
• IRIS is not associated with increased mortality in
patients, except perhaps in resource-limited
settings.
• Patients with CD4<50 may benefit from
immediate ARV therapy
• Serum and CSF cytokine profiles show less
initial inflammation in those who develop IRIS

51. 2010 IDSA Guidelines
• The precision of when to start HAART to avoid IRIS
remains uncertain
• Recommendation 2-10 wks
• Studies by Sungkanuparph (CID 2009) and Zolopa
(PLoS ONE 2009) may favor earlier start but small n’s
• In some settings, long delays in HAART can place
patient at risk of dying from other complications
• Important to anticipate interactions with HAART and
antifungal meds
CID 2010; 50:291–322

52. Back to RG…
• 7/24: Developed L-sided Bell’s Palsy
• 7/27: Low opening pressure, High CrAg CSF
• 7/28: Increasing confusion, Cr 1.8
• 7/30: Tm 101.1. More lethargic and delirious. CT with
progression of meningeal enhancement.
• 7/31: LP with low OP, CSF culture negative
• 8/1: Mentation improved. CSF CMV 2025, Serum CMV
1854, started IV ganciclovir. Cr 1.6
• 8/6 Serum CrAg 1:65,536
• 8/13 CSF CrAg 1:2048 GS mod yeast, culture negative
• 8/16 CSF GS rare yeast, culture negative

53. What ART regimen would you
start?
1. Atripla
2. DRV/r + FTC/TDF
3. RAL + FTC/TDF
4. RAL + DRV/r + ABC/3TC
5. Stribild
6. No clue– help!

54. ART regimen
• Given low CD4 count, high serum and CSF
CrAg, KS on feet and CMV viremia in CSF
Started after anti-fungal induction at 2 weeks
• DVR/r + 3TC/ABC + RAL vs. FTC/TDF + RAL
• No HLA test back +
Desire for simple regimen +
Blood brain barrier porous with several CNS
infections so penetrating regimen less
important +
No reports of IRIS with RAL yet…
• FTC/TDF + RAL started 8/7

55. Hospital Course continued
• Worsening headaches 8/12, repeat LP
8/13 with opening pressure 34
• CSF CrAg 1:2048
• Glucose 39, Protein 50
• WBC 9 (95L, 1S) Glc 39, Prt 50
• CSF GS with rare fungal elements, culture
no growth
• CMV CSF<500

56. Outpatient follow up
• 7/24 Genotype clean
• 8/3 HLAB57 neg
• 9/10 Outpatient visit: Switched to
ABC/3TC + RAL given Cr now 2. CD4
65/9%, VL undetectable (undetectable
8/21)
• Still with facial droop, b/l 6th nerve palsies
improving
• Doing well

57. The plot thickens…
• 10/11 L wrist pain swelling x2 weeks. XR
shows possible occult fracture
• 10/29 MRI: 3 x 2 x 5.5 soft tissue mass
involving scaphoid with extension along
flexor carpi radialis tendon and radial
artery into soft tissues
• 11/5 ortho appointment, bx/aspiration
scheduled for 11/8

58. Fluid aspiration results
• By 11/9, fluid aspirate with HEAVY smear
positivity for AFB!!
• Awaiting culture results but in the
meantime, planning to start 4-drug therapy
+ MAC therapy

59. Thank you!
Special thanks to Gigi Blanchard, Richard
Haubrich and Jennifer Dan.