Wesley Campbell, M.D., of U.S. Navy Medicine, presents "Neurocognitive Changes in Newly Diagnosed Patient with Low CD4: Implications for Prognosis and Employment"
Neurocognitive Changes in Newly Diagnosed Patient with Low CD4: Implications for Prognosis and Employment
1. The UC San Diego AntiViral Research Center sponsors weekly
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researchers. The goal of these presentations is to provide the most
current research, clinical practices and trends in HIV, HBV, HCV, TB
and other infectious diseases of global significance.
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AIDS CLINICAL ROUNDS
2. L T W E S L E Y R . C A M P B E L L , M D
I N F E C T I O U S D I S E A S E S F E L L O W
N A V A L M E D I C A L C E N T E R
S A N D I E G O
HIV Conference
August 30, 2013
3. Disclosures
I have no relevant financial relationships with any
commercial supporters.
Unlabeled/Investigational products and/ or services
will not be mentioned in this CME offering.
4. Objectives
Discuss a case of initial HIV diagnosis
Pose clinically oriented questions
Review the literature as it pertains to this patient
Discuss our treatment plan
5. Case Details
CC: Positive HIV Ab test result
HPI: 23 y/o AD service member without significant
PMH, in usual state of health who was found to be
HIV positive during routine screening.
ROS:
Neg for: nausea, vomiting, fevers, chills, sweats, skin changes
Neg for: CV, pulm, GU, GI symptoms
Denied exposure to blood products or surgeries
7. Case Details
Allergies:
NKDA
SocHx:
Works as an air traffic controller, last deployment in 2011 as part of
Tsunami relief
Unmarried, lives off base, not currently sexually active, last encounter
approximately 1 year prior involving oral sex over a condom
No tobacco, 3-5 alcoholic drinks on weekends
Denies IVDU, illegal drugs, supplements, tattoos
Prev med:
Immunizations: Hep A, Hep B, HPV, IPV, Meningococcal with
Diptheria Conj, Prevnar 13, Tdap, Smallpox, Typhoid (2011), Yellow
Fever
8. Case Details
PE:
VS: 96.8; 80 bpm; (132/73); RR 12; 98% RA
Gen: NAD, mood matches affect
HEENT: Normal without lesions or LAD
CV: Nml with palpable pulses in all 4 extremities
Pulm: Clear to auscultation
Abd: Flat, no HSM, BS+ throughout, no bruit or lesions
Ext: No skin lesions or tattoos, scar in L deltoid from smallpox
CN II-XII without abnormalities, 5/5 strength in all muscle
groups, cerebellar testing without abnormalities, gait normal
9. Labs
Labs
CBC 2.1>16.2/46.5<165 43% neut, 44% lymphs, 12% monos
BMP 140/4.0/101/28/12/1.0<84
LFTs 8.6/4.5/0.5/23/46<66
Lipid Tot 186; Tri 37; HDL46; LDL 133
HIV
Last negative HIV Ab test March 2011
CD4 105/11%; 146/9% repeat
HIV RNA Quant 101,934
Genotype testing: Subtype B, A71T (no resistance detected)
Serologies
Hep A&B immune
CMV negative
VZV IgG negative
Coccidioides serology negative
10. Clinical Questions
With known likely period of seroconversion, what
determined his low CD4 count and viral set point?
As an air traffic controller, what additional concern
is there for current or future emergence of HIV-
associated neurocognitive disorders (HAND)?
Given his occupation, are there considerations for
ART selection?
12. CD4 Count and Set Point
CASCADE database:
Seroconvesion timeline for 3,264 patients (after exclusions
applied: trx naieve, CD4 couts and HIV RNA available,
seroconversion, previous negative HIV)
Worked to est. CD4 rates of decline predict viral load set point
by subtype
Degree of CD4 decline
CD4 decline:
Subtype: B>C>A = CRF02
Women>men; Whites>other ethnicities; Older age>young
Acute infection (seroconversion) had lower CD4 counts but no
greater rate of subsequent decline
Touloumi G, et al. Clin Infect Dis. 2013
13. CD4 Count and Set Point
Discussion:
High viremia subtype B(trend toward older patients), largely
similar viral load set points (see table)
No increased of AIDS or death between subtypes
Cited other studies that looked at other subtypes as
comparison as well as multiple subtype infection as possibly
greater decline in CD4
Touloumi G, et al. Clin Infect Dis. 2013
14. CD4 Count and Set Point
Touloumi G, et al. Clin Infect Dis. 2013
15. CD4 Count and Set Point
Touloumi G, et al. Clin Infect Dis. 2013
17. CD4 Count Decline and Recovery
CASCADE database:
Captured data for treatment naive patients n= 2038
Inclusion at least 2 years CD4 monitoring prior to AR
Didn’t examine genotype
20281 CD4 cell count data points, 2393 pts (only 7 deaths)
CD4 decline:
Pre-ART: 39.3cells/ul/yr (34.3-44.3) in 8-2yrs before ART
96.3 cell/ul/yr (92.3-100.9) in 2 yrs leading up to ART
Steep vs. shallow decline
Steep: 1531 pts >61 cells/ul/yr
Shallow: 507 pts <61cells/ul/yr
Post ART: Shallow vs. Steep slow rate of increase by -45.5 cells/ul/month
SH- 9.5cells/ul/month; steep 13.9 cells/ul/month
Attempted to control for variables- AIDS prior to ART, year of seroconcversion, ,
viral load (were not able to correct for HCV)
Baseline CD4 count and slope of decline sig markers reconstitution
Rate of decline increased with higher CD4 baseline
Proposed a T-cell reserve with high HIV RNA loads, saw greatest rebound in first 4-
6 month
Mussini C, et al. AIDS. 2011
18. HIV-Associated Neurocognitive Disorders
What is the pathophysiology?
What is the epidemiology?
Identified risk factors
Prevalence of neurocognitive impairment (NCI),
neuropsychiatric (NP) impairment
What testing is recommended?
19. Pathophysiology
Post-ART era
Blood-brain-barrier penetration occurs early in HIV infection
Decreased CSF penetration-effectiveness (CPE) for ART
associated with high CSF viral load
CSF “viral escape”
13% in patients with plasma HIV RNA <50 c/ml
“Viral escape” associated with lower CPE of ART
Resnick, et al. Neurology. 1988; Letendre, et al. Arch Neurol. 2010; Rawson T, et
al. J Infect. 2012.
21. Pathophysiology
CSF Viral Escape
142 pts (majority evaluated for HIV encephalopathy, in order
of table)
Correlation with plasma RNA levels and CSF viral load
Rawson T, et al. J Infect. 2012.
25. Pathophysiology
Neuroanatomy
Degraded ability of neuronal plasticity vs. direct inflammation
Spine formation, reorganization in response to injury limited
Propensity for apoptosis
Infected microglial cells activated (HIV vs. dying neurons)
Formation of microglial nodules, giant cells, astrogliosis and
myelin loss
Viral proteins Tat, gp120 associated with direct and indirect
neuronal injury
Synaptic simplification occurs
Avdoshina V, et al. J Intern Med. 2013.
27. Epidemiology
NCI in the post-ART era
With decreased risk of OI, attention shifted to HAND
HAND encompasses: cognitive decline, psycho-motor slowing,
psychiatric disturbances
Prior to ART, HAD estimated prevalence of 5-20%, 7% annual
risk
Post-ART some form of HAND estimated as high as 23.2%,
some estimates currently at 19.8% for mild findings to 50% of
HIV patients
McArthur JC. Medicine. 1987; Jevtovic D. Biomed Pharmacother. 2008; Heaton
RK, et al. Neurology. 2010.
28. NCI and CD4 Count
Odiase F, et al. Can J Neurol Sci. 2007.
29. NCI and CD4 Count
Memory performance in HIV/AIDS
Prospective case control 192 randomly selected HIV patients,
96 symptomatic, and 96 asymptomatic AIDS patients (mostly
20-29 yrs age)
Utilized FePsy testing (controlling for literacy/education, etc…),
Recognition Memory test, attention with choice reaction testing
• Demonstrated nonsignificant impaired memory between controls
and asymptomatic AIDS patients
• Symptomatic AIDS associated with significant impairment
compared to controls
Were able to capture worsening impairment with declining CD4
counts
Odiase F, et al. Can J Neurol Sci. 2007.
30. NCI and CD4 Count
Memory performance in HIV/AIDs
Odiase F, et al. Can J Neurol Sci. 2007.
32. Risk Factors For NCI
Risk Factors
Cohort of 96 patients; on stable ART modified MMSE and
neuro exam
Average CD4<100
Risk
Age>40
Failed treatment response or dissociation
AIDS at diagnosis
Observed worse incidence of HAD in HCV co-infection
Proposed CNS as reservoir
Unable to establish relationship with CD4 count
Jevtovic D. Biomed Pharmacother. 2008.
34. HAND and ART
Cognitive function during treatment interruption
Small cohort study (n=11): on ART NP testing, TI (6 months)
testing, and post resumption of ART testing
Unable to demonstrate decline in NP testing
NP improvements after TI
No demonstrated effect of CD4 nadir to NP results
Childers M, et al. J. Neurovirol. 2008.
36. Medication Adherence
Cognitive changes affect medication adherence
Prospective cohort of 276 HIV-positive adults over 6-month period
NP testing at start, 7 visits with drug screen/reporting, and NP test
out
Authors cited HIV+ only half of pts meet compliance of 90%
adherence
Used MEMS caps with 66% overall adherence rate
• 17% Participants with incomplete data (MEMS data)
• NP decline group more likely to meet substance abuse criteria, but rates
no higher
• 68%tested pos for substance abuse
Global decline of function (T-score driven) associated with
nonadherence with ART
• Adherence declined across every subgroup
• No differences with respect to age, education, CD4 count, length of ART
• Those with low base line GDS had lower rates of NP decline
Becker B, et al. AIDS Behav. 2011.
38. NCI in Early Diagnosis
Crum-Cianflone N, et al. Neurology. 2013.
39. NCI in Early Diagnosis
Neurocognitive impairment in early HIV
Evaluated NCI in early diagnosed HIV infection (median
conversion window 1.2 yrs) in 200 HIV positive patients
compared to HIV negative matched controls
Able to draw on US military data secondary to forcewide
screening to establish early diagnosis
Patient population has open access to medical care and ART
Low rates of comorbid conditions to include substance abuse
Classified by early or late stage based on estimated length of
diagnosis (<6yrs), CD4 nadir (>200), no prior AIDS defining
condition
• Late group: median ll years diagnosed positive
Crum-Cianflone N, et al. Neurology. 2013.
40. NCI in Early Diagnosis
Neurocognitive impairment in early HIV
NCI identified in 38 of 200 HIV-pos patients (early vs. late
stage: 18% vs. 20%, p= 0.72)
No association of self-reported impairment and positive NCI
Patients with depression symptoms were more likely to self
report impairment, but no association with NCI or global
deficit score
30% of non-HIV-infected controls exhibited NCI, and
nonsignificant difference on comparison to HIV infected (p =
0.09)
Crum-Cianflone N, et al. Neurology. 2013.
41. NCI in Early Diagnosis
Crum-Cianflone N, et al. Neurology. 2013.
42. NCI in Early Diagnosis
Risk factors for NCI
No comorbid, behavioral or demographic conditions identified as risk
factors
Higher number of years of education, higher CD4 counts and greater
CD4 recovery, and HIV RNA<50 copies on ART were associated with
NCI
“Marginal” association with CD4 count, but no association degree of
nadir or recovery.
Authors noted
Study population has early diagnosis/treatment, but even late-stage
patients (median of 11yrs diagnosed) showed no significant NCI
differences
Structured supervised work environment/monitoring
ART and undetectable HIV RNA strong association with NCI, but no
association to specific ART regimen
Crum-Cianflone N, et al. Neurology. 2013.
44. Testing For HAND
Research into NCI testing
Testing methodology to identify early neurocognitive
impairment
200 patients subjected to 16 NP battery tests
Military beneficiaries, median age 36.4 yrs
Compared their results to published tests combinations
Utilized validated tests with known population based standards
Compared scores by establishing a T-score scale
Combinations of tests developed with associated sensitivity and
specificity
Moore D, et al. PLoS ONE. 2012.
45. Testing For HAND
Combination testing for HAND
Overall NP impairment 19%
Median CD4 count 546 with 64% on ART
Provided suggestions for use based on time, equipment, and
cost to fit clinical scenarios
Demonstrated limited improvement of sensitivity and
specificity with addition of 4th test
Moore D, et al. PLoS ONE. 2012.
47. Testing For HAND
Screening for HAND
Would like to maximize sensitivity
Verbal learning
Attention/working memory
Processing speed
Moore D, et al. PLoS ONE. 2012.
48. Occupational Considerations
Department of Labor
Unlawful to discriminate based on medical diagnosis of HIV
Do not have to disclose HIV status to your employer
Office of Personnel Management (OPM)/FAA
Air Traffic Control Series 2152 determines employment requirements
(OPM)
No mention of HIV specifically
Unemployable if neurologic condition exists
Aviation Medical Examiners’ guidance
Clear documentation of AIDS complications/resolution
Document achievement of viral load <1,000 copies, and no higher than
5,000 on 6 month follow-ups
3930.3B - Air Traffic Control Specialist Health Program
Meds must be individually approved by Federal Aviation Surgeon
AIDS diagnosis is disqualifying (CDC criteria)
49. Occupational Considerations
US Navy
Restrictions only on special assignments (Spec. Warfare, Subs,
Aviation)
HIV diagnosis and clinical stability on medications drive
occupational assignment
Recent policy modification allows for worldwide assignments
50. Back to Our Patient
HAND
NCI not any more prevalent in early diagnosed and treated
HIV-positive military patients than case-matched controls
Conflicting evidence over direct correlation to CD4 count, but
more likely related HIV activity in the CNS
Goal is to achieve undetectable plasma HIV RNA to decrease
ongoing CNS complications secondary to poor CPE
51. Back to Our Patient
ART choices
Asymptomatic AIDS diagnosis
No direct link of risk to specific ART regimen
Considerations in ART therapy: CD4 count, viral load, side
effects, adherence
52. Applying to the Patient
Treatment approach
Initiated on sulfamethoxazole/trimethoprim prophylaxis
Tenofovir/emtricitabine+darunavir and ritonavir
Evaluate virologic and immune response in 4 weeks
Once on stable therapy-perform NP testing to aid in obtaining
waiver for occupational clearance
53. References
Touloumi G, Pantazis N, Pillay, D, et al. Impact of HIV-1 Subtype on CD4 Count at HIV Seroconversion, Rate of Decline, Viral Load Set Point in European Seroconverter Cohorts. Clin Infect Dis. 2013; 5:
888-898. doi: 10.1093/cid/cis1000
Mussini C, Cossarizza A, Sabin C, et al. Decline of CD4+ T-cell count before start of therapy and immunological response to treatment in antiretroviral-naïve individuals. AIDS. 2011; 25: 1041-1049. doi:
10.1097/QAD.0b013e3283463ec5
Resnick L, Berger JR, Shapshak P, Tourtellotte WW. Early penetration of the blood-brain-barrier by HIV. Neurology. 1988; 38(1): 9-14.
Letendre S, Marquie-Beck J, Capparelli E, et al. Validation of the CNS Penetration-Effectiveness Rank for Quantifying Antiretroviral Penetration into the Central Nervous System. Arch Neurol. 2008; 65(1):
65-70. doi: 10.1001/archneurol.2007.31a
Rawson T, Muir D, Mackie N, Garvey L, Everitt A, Winston A. Factors associated with cerebrospinal fluid HIV RNA in HIV infected subjects undergoing lumbar puncture examination in a clinical setting. J
Infect. 2012; 65(3): 239-245. doi: 10.1016/j.jinf.2012.04.007.
Avdoshina V, Bachis A, Mocchetti I. Synaptic dysfunction in human immunodeficiency virus type-1-positive subjects: inflammation or impaired neuronal plasticity? J Intern Med. 2013; 273(5): 454-465.
doi: 10.1111/joim.12050.
McArthur JC. Neurologic manifestations of AIDS. Medicine. 1987; 66(6): 407-437.
Jevtović DJ, Vanovac V, Veselinović M, Salemović D, Ranin J, Stefanova E. The Incidence of risk factors for HIV-associated cognitive-motor complex among patients on HAART. Biomed
Pharmacother.2008; 63(8): 561-565. doi: 10.1016/j.biopha.2008.09.015.
Heaton RK, Clifford DB, Franklin DR Jr, et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology. 2010;75(23):2087-96. doi:
10.1212/WNL.0b013e318200d727.
Odiase FE, Ogunrin OA, Ogunniyi AA. Memory Performance in HIV/AIDS – A Prospective Case Control Study. Can J Neurol Sci. 2007; 34(2):154-9.
Childers ME, Woods SP, Letendre S, et al. Cognitive functioning during highly active antiretroviral therapy interruption in human immunodeficiency virus type 1 infection. J Neurovirol. 2008; 14(6): 550-
557. doi: 10.1080/13550280802372313.
Becker BW, Thames AD, Woo E, Castellon SA, Hinkin CH. Longitudinal Change in Cognitive Function and Medication Adherence in HIV-Infected Adults. AIDS Behav. 2011; 15(8): 1888-1894. doi:
10.1007/s10461-011-9924-z.
Crum-Cianflone NF, Moore DJ, Letendre S, et al. Low prevalence of neurocognitive impairment in early diagnosed and managed HIV-infected persons. Neurology. 2013; 80(4): 371-379. doi:
10.1212/WNL.0b013e31827f0776.
Moore DJ, Roediger MJ, Eberly LE, et al. Identification of an Abbreviated Test Battery for Detection of HIV-Associated Neurocognitive Impairment in an Early-Managed HIV-Infected Cohort. PLoS ONE.
2012; 7(11): e47310. doi: 10.1371/journal.pone.0047310.
Federal Aviation Administration. Guide for Aviation Medical Examiners. Decision Considerations. Disease Protocols - Human Immunodeficiency Virus (HIV).
http://www.faa.gov/about/office_org/headquarters_offices/avs/offices/aam/ame/guide/dec_cons/disease_prot/hiv/. Accessed August 24, 2013.