Neurocognitive Impairment Symptomatic Peripheral Neuropathy

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					Neurocognitive Impairment, Symptomatic Peripheral Neuropathy and Depression are Highly Prevalent in HIV infected Outpatients within the Asia Pacific Region: Findings of the Asia Pacific NeuroAIDS Consortium (APNAC) Study
Edwina Wright, Bruce Brew, Arkhom Arayawichanont, Kevin Robertson, Kanoksri Samintharapanya, Subsai Kongsaengdao, Megan Lim, Saphonn Vonthanak, Luxshimi Lal, Chel Sarim, Sarah Huffam, Patrick Li, Darma Imran, Jenny Lewis, Wen Hui Lun, Adeeba Kamarulzaman, Goa Tau, Sophaginine Ty Ali, Kamal Kishore, Margaret Bain, Rosamond Dwyer, Gavin McCormack, Margaret Hellard, Kate Cherry, Justin McArthur and Steve Wesselingh on behalf of the APNAC Study Team

The Asia-Pacific NeuroAIDS Consortium
Formed 2002 – PNG – Cambodia – India – Fiji – Indonesia – Thailand – Hong Kong – Singapore – Malaysia – China – Australia

UNAIDS: 2003

Prevalence HIV Neurological Disease in Asia Pacific Region
8.3 million HIV+ people live in the Asia Pacific 3 million people in Asia Pacific Region have advanced, largely untreated HIV disease 2,3
In western countries  1/3 of patients with advanced, untreated HIV disease develop neurological disorders 4 Thus  1 million people at risk of HIV-related neurological disease in AP Region
www.thebody.com/

Region1

1. UNAIDS/WHO, AIDS Epidemic Update Dec 2005; 2. Zhou et al, J Acquir Immune Defic Syndr 2005. 3. UNAIDS/WHO, Progress on Global Access to Antiretroviral therapy. An update on 3X5, Dec 2005. 4. Snider et al Ann Neurol 1983

Exact Prevalence Estimates…
Disorder Prevalence Asia Pacific Region Prevalence western countries pre-HAART 10%- severe 4 25- 30% mild 5

HIV AIDS Dementia

“Uncommon”, 4.6%-11.8% 1,2,3

HIV-related Neurocognitive Impairment
Symptomatic Peripheral Neuropathy

Unknown

40% 6, 7

2.6%-6.4% 1, 2

35% 8

1. Nakagawa et al, Int Med 1997; 2. Oh et al, CID 1999; 3. Satischandra et al, Indian J Med Res 2000; 4. Portegies et al, AIDS 1993; 5. McArthur et al, Neurol 1993; 6. Sacktor et al, J Neurovirol 2002; 7. Cysique et al, Arch Neurol 2004; 8. Schiffito et al, Neurol 2002;

The APNAC Study: Aims
To determine the prevalence of
1. HIV-related Neurocognitive Impairment (NCI) 2. Symptomatic Peripheral neuropathy (SN)

In HIV infected outpatients across the Asia Pacific Region

APNAC Study Methods
• Cross-sectional study at 10 sentinel outpatient sites in 8 APNAC countries • Standardised training at all sites • Enrolled HIV+ outpatients and HIV negative controls for 2-3 week periods

APNAC Study Tools
• Neurocognitive Function
– Neuropsychological test battery1
• • • • Timed gait Grooved pegboard Finger tapper Semantic fluency

– Depression screening tool: CES-D2,3,4 – Alcohol and substance use questionnaire5,6

• Symptomatic Peripheral Neuropathy
– ACTG Peripheral Neuropathy Screening Tool7
1. Price et al, AIDS 1999; 2. Radloff, Appl Psychol Meas 1977; 3. Cockram et al, Aust NZ J Med 1999; 4. Mackinnon et al, J Gerontol B Psychol Sci Soc Sci 1998; 5.NHMRC Australian Alcohol Guidelines, 2001; 6. NIAAA. US Dept Health Human Services 2005 ed. 7. Cherry et al, Neurol 2005.

Study Definitions
• Neurocognitive Impairment
– Patients were defined as impaired if they scored ≥2SDs below the mean scores obtained from local HIV negative controls on two of the four neuropsychological tests1,2,3
• This degree of NCI plus evidence of major functional decline plus no intercurrent condition = HIV Associated Dementia • This degree of NCI alone = moderate-severe neurocognitive impairment

• Depression
– A score >16 on CES-D screening tool4,5,6
1. Grunseit et al, J Clin Exp Neuropyschol 1994; 2. Cysique et al, J Neurovirol 2004; 3. Woods et al, Clin Exp Neuropyschol 2004; 4. Radloff, Appl Psychol Meas 1977; 5. Cockram et al, Aust NZ J Med 1999; Mackinnon et al, J Gerontol B Psychol Sci Soc Sci 1998.

Study Definitions
Symptomatic Peripheral Neuropathy
• Definite
– Symptoms plus absent ankle reflexes plus vibration sense at great toes 10 seconds

• Probable
– Symptoms plus EITHER absent ankle reflexes OR vibration sense at great toes 10 seconds

Results
July 2005 - March 2006 • 658 HIV+ outpatients and 161 HIV- controls enrolled • 10 sites across 8 countries
– 80% ARVs and 65% HAART

APNAC Study Sites

www.lib.utexas.edu

Results: Demography
HIV infected patients n(%) Controls n(%) P-value*

Total
Demographics Gender Male

658

161

390 (59)

90 (56)

Female
Age mean (years) Education
Less than high school, 6yrs High school graduate, 12 yrs Some college/university Bachelor Degree, 15 yrs Postgraduate Degree, 18yrs Unknown
*P-value < 0.05 significant

268 (41)
36
319 (48) 204 (31) 79 (12) 48 (7) 5 (1) 3 (0.5)

71 (44)
34
47 (30) 34 (21) 21 (13) 38 (24) 9 (6) 12 (7)

0.41
0.03 <0.01

Results: Demography
Total HIV+ outpatients n(%) Mode Acquisition n(%) Heterosexual Homosexual Injecting Drug User Blood products Other Unknown Recent CD4 count (n= 593) median (cells/ul) Nadir CD4 count (n=539) median (cells/uL) Prior AIDS illness n(%) 491 (75) 72 (11) 74 (11) 9 (1) 12 (2) 56 (8) 203 IQR (95, 359) 71 IQR (24, 440) 426 (65) 658

Antiretroviral naïve n(%)
Current use of HAART n(%)

107 (16)
414 (65)

Results
• Neurocognitive Impairment: 12%
• 76/647 patients • 35% of patients not receiving HAART

• Depression: 36%
• 235/645 patients • Few patients on antidepressants

• Symptomatic Sensory Neuropathy: 19%
• • • • 126/640 patients Definite (6%) and Probable (13%) 63% patients had prior or current use d-drugs1 26% patients were receiving pain relief

1. d-drugs: stavudine, didanosine or zalcitabine

Risk Factors for NCI, Depression and SN
Total HIV+ outpatients n=658 Age1 mean (years) Diagnosis NCI n/n evaluable (%) Diagnosis depression n/n evaluable (%) Diagnosis SN n/n evaluable (%) Prior AIDS illness n(%) Nadir CD4 cell count median (cells/uL) Current use of HAART n(%) Prior AIDS-related CNS disease n(%) Education level < high school n(%) Excess alcohol use in past 6 months n(%) Substance use in past 6 months n(%) Hepatitis C Ab positive n/n tested (%) Use of d-drugs Current use, Ever used Use of pain relief n/n evaluable (%) Diabetes 3 n(%) Current use anti-tuberculous therapy n(%) Result 36 76/647 (12) 235/645 (36) 126 (19) 426 (65) 71 414 (65) 57 (9) 319 (48%) 7 (1) 25 (4) 51/266 (20) 296 (45), 52 (8) 84/636 (13) 15 (2) 167 (25) NCI P-value* <0.01 --0.11 <0.01 <0.01 0.93 0.84 0.54 0.08 # # 0.79 --0.06 ----Depression P-value 0.19 0.11 --0.02 <0.01 0.58 0.49 0.24 <0.01 # # 0.19 --0.63 ----SN P-value <0.01 <0.01 0.01 --0.01 0.45 <0.01 0.96 0.28 # # 0.94 0.01, <0.01 <0.01 0.15 0.68

1. Univariate analysis: Age:>35 years; 2. Univariate analysis: CD4 nadir (mean):> 80 cells/uL ; 3. Diabetes: defined as diagnosis of diabetes or use of diabetic drugs; # numbers too small to be included in univariate analysis. * significance= p value < 0.05

Risk Factors for NCI, Depression and SN
Total HIV+ outpatients n=658 NCI Adjusted OR 95%CI P-value 1.85 (1.08,3.15) 0.02 --ns 2.24 (1.28,3.91) <0.01 Depression Adjusted OR 95%CI P-value ns ns --1.54 (1.19, 3.79) 0.01 SN Adjusted OR 95%CI P-value 1.81 (1.18, 2.77) <0.01 2.16 (1.23, 3.80) <0.01 ns ---

Age >35 years Diagnosis NCI Diagnosis depression Diagnosis SN

Prior AIDS illness
Education level < high school Use of d-drugs Current Ever Use of pain relief

2.05 (1.11,3.76) 0.02
0.02 ---

1.63 (1.12, 2.37) 0.01
1.67 (1.19, 2.35) <0.01 ---

ns
ns ns 3.2 (1.56, 6.55) <0.01 3.18 (1.90, 5.32) <0.01

ns

ns

Discussion
• First study within the Asia Pacific Region to report the likely burden of – HIV-related Neurocognitive Impairment – Symptomatic Sensory Neuropathy – Depression • Broad relevance of these findings to the AP Region
– Up to 1.0 million people may have HIV associated dementia – 1.5 million people may have symptomatic sensory neuropathy – Over 1/3 HIV infected patients may have depression

Discussion
Further relevance findings
• • • • NCI, Depression and SN under-diagnosed NCI and depression => Poor adherence1,2 NCI=>Increased risk job loss3 Alternative treatment options required

•

Evidence-based treatment strategies required for Asia Pacific region

1. Hinkin et al, Nat Med 2002; 2. Yun et al, J Acquir Immune Defic Syndr 2005; 3. Albert et al, Arch Neurol 1995

Summary
• HIV-related neurocognitive impairment, depression and symptomatic peripheral neuropathy are highly prevalent in the Asia Pacific Region • These findings have implications regarding treatment options and the need for further research to inform current and future treatment strategies

Dept Medicine, Sappasithiprasong Hospital, Ubonratchathani, Thailand Arkhom Arayawichanont

APNAC Study Team

Beijing Ditan Hospital, Beijing, China Wen Hui Lun, Guang Zeng, Key Xu University Malaya Medical Center, Kuala Lumpur, Malaysia Adeeba Kamarulzaman, Clarence Sim Port Moresby General Hospital, Port Moresby PNG Goa Tau Reproductive Health Clinic and Colonial War Memorial Hospital, Suva Fiji Sophaginine Ty Ali, Kamal Kishore Dept Neurology, The Johns Hopkins Hospital, Baltimore, USA Justin McArthur, Sandy Zhang

Dept Neurology, University North Carolina, NC USA Kevin Robertson Dept Internal Medicine, Division of Neurology, Lumpang Hospital, Muang District, Thailand Kanoksri Samintarapanya, Panita Pathipvanich Division of Neurology, Dept Medicine, Rajavithi Hospital Bangkok, Thailand Subsai Kongsaengdao

National Centre HIV/AIDS, STD and Dermatology St Vincent’s Hospital, Sydney, Australia Bruce Brew, Social Health Clinic, Phnom Penh Cambodia Saphonn Vonthanak, Chel Sarim, Sarah Huffam Margaret Peggy Bain Queen Elizabeth Hospital, Hong Kong Patrick Li, Iris Chen Dr Cipto Mangunkusomo Hospital, Jakarta, Indonesia Darma Imran, Jofizal Jannis

Burnet Institute, Melbourne, Australia Steve Wesselingh, Luxshimi Lal, Megan Lim, Jenny Lewis, Darshini Devadson, Margaret Hellard, Gavin McCormack The Alfred Hospital, Melbourne, Australia Rosamond Dwyer, Craig Scholten, Teresa Girke, Jenny Hoy, Sharon Lewin, Edwina Wright

Study funded by NINDS and NIMH, NIH

Study Definitions: Depression, Substance and Alcohol Use
• Significant risk of underlying depression
– Score > 16 on CESD-20 Screening tool

• Excess alcohol intake
– More than 4 standard drinks on 4-7 days per week in preceding 6 months

• Significant substance use
– Use of amphetamines, heroin, ketamine, LSD, marijuana, MDMA, methamphetamine, PCP, crack cocaine in the preceding 6 months

Study Numbers
Outpatients required Peripheral neuropathy Neurocognitive impairment 370 Predicted prevalence 15%* 95% confidence intervals 11.2-18.5

370

15%*

11.2-18.5

Statistical Methods
• Controls
– Student t-test and chi-square

• Univariate analysis
– Chi-square test and Fisher’s exact test – Current CD4 cells < 200/uL, Nadir CD4 cell count, Prior ADI, Prior CNS AIDS illness, Prior head injury, Education level less than high school, CESD score >16, Use of pain medication, Use of ARVs (none, <3, >3), Use of neuroHAART, Hepatitis C antibody positivity, Diagnosis of SN, Diagnosis of NCI

• Multivariate analysis
– Logistic regression

PN screening in APNAC study


				
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