Wesley Campbell, M.D., of U.S. Navy Medicine, presents "Neurocognitive Changes in Newly Diagnosed Patient with Low CD4: Implications for Prognosis and Employment"

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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

6. Case Details
 PMH:
 None
 PSH:
 None
 Meds:
 Occasional Ibuprofen

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?

11. CD4 Count and Set Point

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

16. CD4 Count Decline and Recovery
Mussini C, et al. AIDS. 2011

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.

20. Pathophysiology

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.

22. Pathophysiology
Rawson T, et al. J Infect. 2012.

23. Pathophysiology
Rawson T, et al. J Infect. 2012.

24. Pathophysiology
Avdoshina V, et al. J Intern Med. 2013.

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.

26. Pathophysiology
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.

31. Risk Factors For NCI
Jevtovic D. Biomed Pharmacother. 2008.

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.

33. HAND and ART
Childers M, et al. J. Neurovirol. 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.

35. Medication Adherence
Becker B, et al. AIDS Behav. 2011.

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.

37. Medication Adherence
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.

43. Testing For HAND
Moore D, et al. PLoS ONE. 2012.

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.

46. Testing For HAND
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.